tag:theconversation.com,2011:/us/topics/gene-therapy-5256/articlesGene therapy – The Conversation2024-03-27T19:07:40Ztag:theconversation.com,2011:article/2263932024-03-27T19:07:40Z2024-03-27T19:07:40ZThe first pig kidney has been transplanted into a living person. But we’re still a long way from solving organ shortages<figure><img src="https://images.theconversation.com/files/584634/original/file-20240327-22-zkx0ie.jpg?ixlib=rb-1.1.0&rect=0%2C73%2C8192%2C5383&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.massgeneral.org/news/press-release/worlds-first-genetically-edited-pig-kidney-transplant-into-living-recipient">Massachusetts General Hospital</a></span></figcaption></figure><p>In a world first, we heard last week that US surgeons had transplanted a kidney from a gene-edited pig into a living human. News reports said the procedure was <a href="https://www.npr.org/sections/health-shots/2024/03/21/1239790816/first-pig-kidney-human-transplant">a breakthrough</a> in xenotransplantation – when an organ, cells or tissues are transplanted from one species to another.</p>
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<figcaption><span class="caption">The world’s first transplant of a gene-edited pig kidney into a live human was announced last week.</span></figcaption>
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<p>Champions of xenotransplantation regard it as <em>the</em> solution to organ shortages across the world. In December 2023, <a href="https://www.anzdata.org.au/anzod/publications-2/organ-waiting-list/">1,445 people</a> in Australia were on the waiting list for donor kidneys. In the United States, more than <a href="https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/">89,000</a> are waiting for kidneys. </p>
<p>One biotech CEO says gene-edited pigs <a href="https://www.technologyreview.com/2015/08/12/248193/surgeons-smash-records-with-pig-to-primate-organ-transplants/">promise</a> “an unlimited supply of transplantable organs”.</p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452271/">Not</a>, <a href="https://theconversation.com/organ-transplants-from-pigs-medical-miracle-or-pandemic-in-the-making-175290">everyone</a>, though, <a href="https://onlinelibrary.wiley.com/doi/10.1111/imj.13183">is convinced</a> transplanting animal organs into humans is really the answer to organ shortages, or even if it’s right to use organs from other animals this way.</p>
<p>There are two critical barriers to the procedure’s success: organ rejection and the transmission of <a href="https://journals.sagepub.com/doi/epdf/10.1177/09636897241226849">animal viruses to recipients</a>. </p>
<p>But in the past decade, a new platform and technique known as CRISPR/Cas9 – often shortened to CRISPR – has promised to mitigate these issues.</p>
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Read more:
<a href="https://theconversation.com/organ-transplants-from-pigs-medical-miracle-or-pandemic-in-the-making-175290">Organ transplants from pigs: Medical miracle or pandemic in the making?</a>
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<h2>What is CRISPR?</h2>
<p>CRISPR gene editing takes advantage of a system already found in nature. CRISPR’s “genetic scissors” evolved in bacteria and other microbes to help them fend off viruses. Their cellular machinery <a href="https://www.sciencedirect.com/science/article/pii/S0300908415001042#:%7E:text=The%20system%2C%20called%20CRISPR%2DCas,remember%2C%20recognize%20and%20clear%20infections.">allows them</a> to integrate and ultimately destroy viral DNA by cutting it.</p>
<p>In 2012, two teams of scientists <a href="https://www.science.org/doi/10.1126/science.1225829">discovered how to harness</a> this bacterial immune system. This is made up of repeating arrays of DNA and associated proteins, known as “Cas” (CRISPR-associated) proteins. </p>
<p>When they used a particular Cas protein (Cas9) with a “guide RNA” made up of a singular molecule, they found they could <a href="https://pubmed.ncbi.nlm.nih.gov/22745249/">program</a> the CRISPR/Cas9 complex to break and repair DNA at precise locations as they desired. The system could even “knock in” new genes at the repair site. </p>
<p>In 2020, the two scientists leading these teams were awarded a <a href="https://www.nobelprize.org/prizes/chemistry/2020/summary/">Nobel prize</a> for their work.</p>
<p>In the case of the latest xenotransplantation, CRISPR technology was used to <a href="https://www.massgeneral.org/news/press-release/worlds-first-genetically-edited-pig-kidney-transplant-into-living-recipient">edit 69 genes</a> in the donor pig to inactivate viral genes, “humanise” the pig with human genes, and knock out harmful pig genes.</p>
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<figcaption><span class="caption">How does CRISPR work?</span></figcaption>
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Read more:
<a href="https://theconversation.com/what-is-crispr-the-gene-editing-technology-that-won-the-chemistry-nobel-prize-147695">What is CRISPR, the gene editing technology that won the Chemistry Nobel prize?</a>
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<h2>A busy time for gene-edited xenotransplantation</h2>
<p>While CRISPR editing has brought new hope to the possibility of xenotransplantation, even recent trials show great caution is still warranted.</p>
<p>In 2022 and 2023, two patients with <a href="https://www.medschool.umaryland.edu/news/2023/um-medicine-faculty-scientists-and-clinicians-perform-second-historic-transplant-of-pig-heart-into-patient-with-end-stage-cardiovascular-disease.html#:%7E:text=The%20first%20historic%20surgery%2C%20performed,had%20end%2Dstage%20heart%20disease.">terminal heart diseases</a>, who were ineligible for traditional heart transplants, were granted <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00775-4/abstract">regulatory permission</a> to receive a gene-edited pig heart. These pig hearts had ten genome edits to make them more suitable for transplanting into humans. However, both patients died within several weeks of the procedures. </p>
<p>Earlier this month, we heard a team of surgeons in China transplanted a gene-edited pig liver into a <a href="https://www.nature.com/articles/d41586-024-00853-8">clinically dead man</a> (with family consent). The liver functioned well up until the ten-day limit of the trial.</p>
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Read more:
<a href="https://theconversation.com/you-donate-your-body-to-science-you-die-what-happens-next-1481">You donate your body to science, you die ... what happens next?</a>
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<h2>How is this latest example different?</h2>
<p>The gene-edited pig kidney <a href="https://www.massgeneral.org/news/kidney-xenotransplant-faqs">was transplanted</a> into a relatively young, living, legally competent and consenting adult.</p>
<p>The total number of gene edits edits made to the donor pig is very high. The researchers report making <a href="https://www.nature.com/articles/d41586-024-00879-y">69 edits</a> to inactivate viral genes, “humanise” the pig with human genes, and to knockout harmful pig genes.</p>
<p>Clearly, the race to transform these organs into viable products for transplantation is ramping up.</p>
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Read more:
<a href="https://theconversation.com/what-are-uterus-transplants-who-donates-their-uterus-and-what-are-the-risks-190443">What are uterus transplants? Who donates their uterus? And what are the risks?</a>
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<h2>From biotech dream to clinical reality</h2>
<p>Only a few months ago, CRISPR gene editing made its debut in mainstream medicine. </p>
<p>In November, drug regulators in the <a href="https://www.gov.uk/government/news/mhra-authorises-world-first-gene-therapy-that-aims-to-cure-sickle-cell-disease-and-transfusion-dependent-thalassemia">United Kingdom</a> and <a href="https://www.fda.gov/media/174618/download?attachment">US</a> approved the world’s first CRISPR-based genome-editing therapy for human use – a treatment for life-threatening forms of sickle-cell disease. </p>
<p>The treatment, known as <a href="https://sicklecellanemianews.com/ctx001-sickle-cell-disease">Casgevy</a>, uses CRISPR/Cas-9 to edit the patient’s own blood (bone-marrow) stem cells. By disrupting the <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2029392">unhealthy gene</a> that gives red blood cells their “sickle” shape, the aim is to produce red blood cells with a healthy spherical shape. </p>
<p>Although the treatment uses the patient’s own cells, the same underlying principle applies to recent clinical xenotransplants: unsuitable cellular materials may be edited to make them therapeutically beneficial in the patient.</p>
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<a href="https://images.theconversation.com/files/584639/original/file-20240327-26-b7jv5t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Sickle cells have a different shape to healthy round red blood cells" src="https://images.theconversation.com/files/584639/original/file-20240327-26-b7jv5t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/584639/original/file-20240327-26-b7jv5t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=337&fit=crop&dpr=1 600w, https://images.theconversation.com/files/584639/original/file-20240327-26-b7jv5t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=337&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/584639/original/file-20240327-26-b7jv5t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=337&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/584639/original/file-20240327-26-b7jv5t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/584639/original/file-20240327-26-b7jv5t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/584639/original/file-20240327-26-b7jv5t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">CRISPR technology is aiming to restore diseased red blood cells to their healthy round shape.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/3d-rendered-medical-illustration-sickle-cell-2221001799">Sebastian Kaulitzki/Shutterstock</a></span>
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Read more:
<a href="https://theconversation.com/organs-too-risky-to-donate-may-be-safer-than-we-think-we-crunched-the-numbers-and-heres-what-we-found-124993">Organs 'too risky' to donate may be safer than we think. We crunched the numbers and here's what we found</a>
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<h2>We’ll be talking more about gene-editing</h2>
<p>Medicine and gene technology regulators are increasingly asked to <a href="https://www.utas.edu.au/__data/assets/pdf_file/0011/1634258/OP12-final-report.pdf">approve new experimental trials</a> using gene editing and CRISPR.</p>
<p>However, neither xenotransplantation nor the therapeutic applications of this technology lead to changes to the genome that can be inherited.</p>
<p>For this to occur, CRISPR edits would need to be applied to the cells at the earliest stages of their life, such as to <a href="https://doi.org/10.1089/crispr.2020.0082">early-stage embryonic cells</a> in vitro (in the lab). </p>
<p>In Australia, intentionally creating heritable alterations to the human genome is a criminal offence carrying <a href="https://classic.austlii.edu.au/au/legis/cth/consol_act/pohcfra2002465/s15.html">15 years’ imprisonment</a>. </p>
<p><a href="https://www.utas.edu.au/__data/assets/pdf_file/0011/1634258/OP12-final-report.pdf">No jurisdiction in the world</a> has laws that <a href="https://doi.org/10.1089/crispr.2020.0082">expressly permits</a> heritable human genome editing. However, some <a href="https://crispr-gene-editing-regs-tracker.geneticliteracyproject.org/russia-germline-embryonic/">countries</a> lack specific regulations about the procedure.</p>
<h2>Is this the future?</h2>
<p>Even without creating inheritable gene changes, however, xenotransplantation using CRISPR is in its infancy.</p>
<p>For all the promise of the headlines, there is not yet one example of a stable xenotransplantation in a living human lasting <a href="https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.03060/full">beyond seven months</a>. </p>
<p>While authorisation for this recent US transplant has been granted under the so-called “compassionate use” <a href="https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.310">exemption</a>, conventional clinical trials of pig-human xenotransplantation have yet to commence. </p>
<p>But the prospect of such trials would likely require significant improvements in current outcomes to gain regulatory approval <a href="https://www.fda.gov/media/102126/download">in the US</a> or <a href="https://iris.who.int/bitstream/handle/10665/341817/WHO-HTP-EHT-CPR-2011.01-eng.pdf?sequence=1&isAllowed=y">elsewhere</a>. </p>
<p>By the same token, regulatory approval of any “off-the-shelf” xenotransplantation organs, including gene-edited kidneys, would seem <a href="https://link.springer.com/chapter/10.1007/978-981-99-7691-1_24">some way off</a>.</p><img src="https://counter.theconversation.com/content/226393/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Christopher Rudge was a member of a research team that designed and convened an Australian citizens' jury on genome editing in 2021-22. This was funded by the Medical Research Future Fund.</span></em></p>Champions of xenotransplantation see it as the solution to organ shortages across the world. But this technology has other applications.Christopher Rudge, Law lecturer, University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2113962023-11-29T13:38:49Z2023-11-29T13:38:49ZMicroRNA is the master regulator of the genome − researchers are learning how to treat disease by harnessing the way it controls genes<figure><img src="https://images.theconversation.com/files/561973/original/file-20231127-27-vqtw0l.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1400&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">RNA is more than just a transitional state between DNA and protein.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/molecule-of-mrna-illustration-royalty-free-illustration/1450368774">Kateryna Kon/Science Photo Library via Getty Images</a></span></figcaption></figure><p>The Earth <a href="https://www.scientificamerican.com/article/evolution-of-earth/">formed 4.5 billion years ago</a>, and life less than a billion years after that. Although life as we know it is <a href="https://sciencing.com/abundant-organic-compound-earth-22851.html">dependent on four major macromolecules</a> – DNA, RNA, proteins and lipids – only one is thought to have been present at the beginning of life: RNA. </p>
<p>It is no surprise that <a href="https://www.khanacademy.org/science/ap-biology/natural-selection/origins-of-life-on-earth/a/rna-world">RNA likely came first</a>. It is the only one of those major macromolecules that can both replicate itself and catalyze chemical reactions, both of which are essential for life. Like DNA, RNA is made from individual nucleotides linked into chains. Scientists initially understood that genetic information flows in one direction: DNA is transcribed into RNA, and RNA is translated into proteins. That principle is called the <a href="https://www.genome.gov/genetics-glossary/Central-Dogma">central dogma of molecular biology</a>. But there are many deviations.</p>
<p>One major example of an exception to the central dogma is that some RNAs are never translated or coded into proteins. This fascinating diversion from the central dogma is what led me to <a href="https://scholar.google.com/citations?user=4JMQMLgAAAAJ&hl=en">dedicate my scientific career</a> to understanding how it works. Indeed, research on RNA has lagged behind the other macromolecules. Although there are multiple classes of these so-called noncoding RNAs, researchers like myself have started to focus a great deal of attention on short stretches of genetic material called <a href="https://www.ibiology.org/genetics-and-gene-regulation/introduction-to-micrornas/">microRNAs</a> and their potential to treat various diseases, including cancer.</p>
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<figcaption><span class="caption">MicroRNAs play a key role in regulating gene expression.</span></figcaption>
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<h2>MicroRNAs and disease</h2>
<p>Scientists regard microRNAs as <a href="https://doi.org/10.1146/annurev-pharmtox-010510-100517">master regulators of the genome</a> due to their ability to bind to and alter the expression of many protein-coding RNAs. Indeed, a single microRNA can regulate anywhere from 10 to 100 protein-coding RNAs. Rather than translating DNA to proteins, they instead can bind to protein-coding RNAs to silence genes. </p>
<p>The reason microRNAs can regulate such a diverse pool of RNAs stems from their ability to bind to target RNAs they don’t perfectly match up with. This means a single microRNA can often regulate a pool of targets that are all involved in similar processes in the cell, leading to an enhanced response.</p>
<p>Because a single microRNA can regulate multiple genes, many microRNAs can contribute to disease when they become dysfunctional.</p>
<p>In 2002, researchers first identified the role dysfunctional microRNAs play in disease through patients with a type of blood and bone marrow cancer called <a href="https://doi.org/10.1073/pnas.242606799">chronic lymphocytic leukemia</a>. This cancer results from the <a href="https://doi.org/10.1038/cdd.2009.69">loss of two microRNAs</a> normally involved in blocking tumor cell growth. Since then, scientists have identified <a href="https://mirbase.org/browse/results/?organism=hsa">over 2,000 microRNAs in people</a>, many of which are altered in various diseases. </p>
<p>The field has also developed a fairly solid understanding of how microRNA dysfunction contributes to disease. Changing one microRNA can change several other genes, resulting in a plethora of alterations that can collectively reshape the cell’s physiology. For example, over half of all cancers have significantly reduced activity in a <a href="https://doi.org/10.3389/fcell.2021.640587">microRNA called miR-34a</a>. Because miR-34a regulates many genes involved in preventing the growth and migration of cancer cells, losing miR-34a can increase the risk of developing cancer.</p>
<p>Researchers are looking into using microRNAs as therapeutics for cancer, heart disease, neurodegenerative disease and others. While results in the laboratory have been promising, bringing microRNA treatments into the clinic has <a href="https://doi.org/10.1016/j.tig.2022.02.006">met multiple challenges</a>. Many are related to inefficient delivery into target cells and poor stability, which limit their effectiveness.</p>
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<span class="caption">MicroRNA can silence genes by binding to mRNA.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Conceptual_overview_of_multiomics_-_digital_skewed.png">Kajsa Mollersen/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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<h2>Delivering microRNA to cells</h2>
<p>One reason why delivering microRNA treatments into cells is difficult is because microRNA treatments need to be delivered specifically to diseased cells while avoiding healthy cells. Unlike <a href="https://theconversation.com/how-mrna-and-dna-vaccines-could-soon-treat-cancers-hiv-autoimmune-disorders-and-genetic-diseases-170772">mRNA COVID-19 vaccines</a> that are taken up by scavenging immune cells whose job is to detect foreign materials, microRNA treatments need to fool the body into thinking they aren’t foreign in order to avoid immune attack and get to their intended cells.</p>
<p>Scientists are studying various ways to deliver microRNA treatments to their specific target cells. One method garnering a great deal of attention relies on directly <a href="https://doi.org/10.1093/narcan/zcab030">linking the microRNA to a ligand</a>, a kind of small molecule that binds to specific proteins on the surface of cells. Compared with healthy cells, diseased cells can have a disproportionate number of some surface proteins, or receptors. So, ligands can help microRNAs home specifically to diseased cells while avoiding healthy cells. The first ligand approved by the U.S. Food and Drug Administration to deliver small RNAs like microRNAs, <a href="https://doi.org/10.1007/s40265-020-01269-0">N-acetylgalactosamine, or GalNAc</a>, preferentially delivers RNAs to liver cells.</p>
<p>Identifying ligands that can deliver small RNAs to other cells requires finding receptors expressed at high enough levels on the surface of target cells. Typically, <a href="https://doi.org/10.1038/nrd4519">over one million copies per cell</a> are needed in order to achieve sufficient delivery of the drug.</p>
<p>One ligand that stands out is <a href="https://theconversation.com/adding-folic-acid-to-staple-foods-can-prevent-birth-defects-but-most-countries-dont-do-it-55533">folate, also referred to as vitamin B9</a>, a small molecule critical during periods of rapid cell growth such as fetal development. Because some tumor cells have over one million folate receptors, this ligand provides sufficient opportunity to deliver enough of a therapeutic RNA to target different types of cancer. For example, my laboratory developed a new molecule <a href="https://doi.org/10.1126/scitranslmed.aam9327">called FolamiR-34a</a> – folate linked to miR-34a – that reduced the size of breast and lung cancer tumors in mice.</p>
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<a href="https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image juxtaposing endothelial cells sprouting extensions to form new blood vessels and a cell bathed in microRNA unable to sprout" src="https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=387&fit=crop&dpr=1 600w, https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=387&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=387&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=486&fit=crop&dpr=1 754w, https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=486&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/561976/original/file-20231127-18-5pbfrd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=486&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Tumors can exploit healthy cells to grow blood vessels that provide them nutrients, as seen in the endothelial cells to the left sprouting extensions. Exposing these cells to certain microRNAs, however, can disable that growth, as seen in the cell to the right.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/2hrJ3g4">Dudley Lab, University of Virginia School of Medicine/NIH via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
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<h2>Making microRNAs more stable</h2>
<p>One of the other challenges with using small RNAs is their <a href="https://doi.org/10.1093/narcan/zcab030">poor stability</a>, which leads to their rapid degradation. As such, RNA-based treatments are generally short-lived in the body and require frequent doses to maintain a therapeutic effect. </p>
<p>To overcome this challenge, researchers are <a href="https://doi.org/10.1093/narcan/zcab030">modifying small RNAs</a> in various ways. While each RNA requires a specific modification pattern, successful changes can <a href="https://doi.org/10.1038/s41388-023-02801-8">significantly increase their stability</a>. This reduces the need for frequent dosing, subsequently decreasing treatment burden and cost. </p>
<p>For example, <a href="https://doi.org/10.1089%2Fnat.2018.0736">modified GalNAc-siRNAs</a>, another form of small RNAs, reduces dosing from every few days to once every six months in nondividing cells. My team developed <a href="https://doi.org/10.1038/s41388-023-02801-8">folate ligands</a> linked to modified microRNAs for cancer treatment that reduced dosing from once every other day to once a week. For diseases like cancer where cells are rapidly dividing and quickly diluting the delivered microRNA, this increase in activity is a significant advancement in the field. We anticipate this accomplishment will facilitate further development of this folate-linked microRNA as a cancer treatment in the years to come.</p>
<p>While there is still considerable work to be done to overcome the hurdles associated with microRNA treatments, it’s clear that RNA shows promise as a therapeutic for many diseases.</p><img src="https://counter.theconversation.com/content/211396/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrea Kasinski receives funding from the National Institutes of Health, Department of Defense, and the American Lung Association. Kasinski is also the inventor on multiple patients associated with her discoveries in the RNA therapeutics field. </span></em></p>When just one of the thousands of microRNAs in people go awry, it can cause diseases ranging from heart disease to cancer.Andrea Kasinski, Associate Professor of Biological Sciences, Purdue UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2005262023-05-12T12:19:21Z2023-05-12T12:19:21ZGene therapy helps combat some forms of blindness – and ongoing clinical trials are looking to extend these treatments to other diseases<figure><img src="https://images.theconversation.com/files/517754/original/file-20230327-14-rcucem.jpg?ixlib=rb-1.1.0&rect=24%2C18%2C997%2C490&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">New gene therapies are helping to treat certain forms of inherited blindness.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/view-of-a-blind-man-assisted-by-a-friend-as-he-walks-on-a-news-photo/1299277661?phrase=blind%20person%20walking&adppopup=true">GettyImages</a></span></figcaption></figure><p><em><a href="https://www.orbis.org/en/news/2021/new-global-blindness-data#">An estimated 295 million people</a> suffer from visual impairment globally. Around 43 million of those people are living with blindness. While not every form of blindness can be cured, <a href="https://pubmed.ncbi.nlm.nih.gov/33278565/">recent scientific breakthroughs</a> have uncovered new ways to treat some forms of inherited blindness through gene therapy.</em></p>
<p><em><a href="https://www.med.upenn.edu/apps/faculty/index.php/g275/p11214">Jean Bennett</a> is a gene therapy expert and a professor emeritus of ophthalmology at the University of Pennsylvania. She and her laboratory developed the first gene therapy drug for a genetic disease to be approved in the U.S. The drug, <a href="https://luxturna.com/">Luxturna</a>, treats patients with biallelic RPE65 mutation-associated retinal dystrophy, a rare genetic disorder that causes visual impairments and blindness in patients early in life.</em></p>
<p><em>In March, Bennett spoke at the 2023 <a href="https://www.imaginesolutionsconference.com/">Imagine Solutions Conference</a> in Naples, Florida, about what gene therapy is, why it matters and the success she and her team have had helping the blind to see. The Conversation caught up with Bennett after the conference. Her edited answers are below.</em></p>
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<figcaption><span class="caption">Jean Bennett speaks at the 2023 Imagine Solutions Conference.</span></figcaption>
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<h2>What is gene therapy and how does it work?</h2>
<p><a href="https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy">Gene therapy</a> is a set of techniques that harness <a href="https://medlineplus.gov/genetics/understanding/basics/dna/">DNA</a> or <a href="https://www.umassmed.edu/rti/biology/what-is-rna/">RNA</a> to treat or prevent disease. Gene therapy treats disease in <a href="https://www.childrenshospital.org/treatments/gene-therapy#">three primary ways</a>: by substituting a disease-causing gene with a healthy new or modified copy of that gene; turning genes on or off; and injecting a new or modified gene into the body.</p>
<h2>How has gene therapy changed how doctors treat genetic eye diseases and blindness?</h2>
<p>In the past, many doctors did not think it necessary to identify the genetic basis of eye disease because treatment was not yet available. However, a few specialists, including <a href="https://www.med.upenn.edu/carot/">me and my collaborators</a>, identified these defects in our research, convinced that someday treatment would be made possible. Over time, we were able to create a treatment designed for individuals with particular gene defects that lead to congenital blindness.</p>
<p>This development of gene therapy for inherited disease has <a href="https://www.eye-tuebingen.de/wissingerlab/projects/rd-cure/">inspired</a> <a href="https://atsenatx.com/">other</a> <a href="https://www.medicalnewstoday.com/articles/gene-therapy-for-macular-degeneration">groups</a> around the world to initiate clinical trials targeting other genetic forms of blindness, such as <a href="https://medlineplus.gov/genetics/condition/choroideremia/">choroideremia</a>, <a href="https://medlineplus.gov/genetics/condition/achromatopsia/">achromatopsia</a>, <a href="https://medlineplus.gov/genetics/condition/retinitis-pigmentosa/">retinitis pigmentosa</a> and even <a href="https://www.hopkinsmedicine.org/health/conditions-and-diseases/agerelated-macular-degeneration-amd">age-related macular degeneration</a>, all of which lead to vision loss. There are at least <a href="https://www.clinicaltrials.gov/">40 clinical trials</a> enrolling patients with other genetic forms of blinding disease. </p>
<p>Gene therapy treatments are now available in pharmacies and operating rooms all over the world. </p>
<p>Gene therapy is even being used to restore vision to people whose photoreceptors – the cells in the retina that respond to light – have completely degenerated. This approach uses <a href="https://pubmed.ncbi.nlm.nih.gov/36499371/">optogenetic therapy</a>, which aims to revive those degenerated photoreceptors by adding light-sensing molecules to cells, thereby drastically improving a person’s vision.</p>
<h2>You created one of the first gene therapies approved in the US. What is the current state of the clinical use of gene therapy?</h2>
<p>There are now many approved gene therapies in the U.S., but the majority are combined with cell therapies in which a cell is modified in a dish and then injected back into the patient. </p>
<figure class="align-left ">
<img alt="Woman in lab coat, face mask, goggles and gloves squeezes syringe into petri dish" src="https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/512977/original/file-20230301-1750-ujq9ka.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Many forms of gene therapy are helping to treat blindness.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/asian-female-doctor-is-working-in-laboratory-royalty-free-image/1363580438?phrase=laboratory%20technician&adppopup=true">GettyImages</a></span>
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<p>The majority of those therapies target different forms of cancer, although there are several for devastating inherited diseases. The drug <a href="https://www.fda.gov/vaccines-blood-biologics/skysona">Skysona</a> is a new injectable gene therapy medication that treats boys ages 4 to 17 with <a href="https://www.childrenshospital.org/conditions/adrenoleukodystrophy-ald">cerebral adrenoleukodystrophy</a>, a genetic disease in which a buildup of very-long-chain fatty acids in the brain can lead to death.</p>
<p>The gene therapy that my team and I developed was the first FDA-approved project involving injection of a gene therapy directly into a person – in this case, into the retina. Only one other <a href="https://www.fda.gov/vaccines-blood-biologics/zolgensma">FDA-approved gene therapy</a> is directly administered to the body – one that targets <a href="https://www.hopkinsmedicine.org/health/conditions-and-diseases/spinal-muscular-atrophy-sma#">spinal muscular atrophy</a>, a disease that causes progressive muscle weakness and eventually death. The drug, Zolgensma, is injected intravenously into babies and children diagnosed with the disease, allowing them to live as healthy, active children. </p>
<p>There are now more than two dozen FDA-approved cell and gene therapies, including <a href="https://theconversation.com/anti-cancer-car-t-therapy-reengineers-t-cells-to-kill-tumors-and-researchers-are-expanding-the-limited-types-of-cancer-it-can-target-196471">CAR T-cell therapies</a> – in which T cells, a type of immune system cells, are modified in the laboratory to better attack cancer cells in the body – and therapies for various blood diseases.</p>
<h2>What are you currently working on that you’re most excited about?</h2>
<p>I am very excited about some <a href="https://clinicaltrials.gov/ct2/show/NCT05616793?cond=LCA5&draw=2&rank=1">upcoming clinical trials</a> that my team will soon initiate to target some other devastating blinding diseases. We will incorporate a new test of functional vision – how your eyes, brain and the visual pathways between them work together to help a person move in the world. This test utilizes a virtual reality game that is not only fun for the user but promises to provide an objective measure of the person’s functional vision. I hope that our virtual reality test will inform us of any potential benefits from the treatments and also serve as a useful outcome measure for other gene and cell therapy clinical trials involving vision.</p>
<h2>What are the biggest challenges gene therapy faces?</h2>
<p>The biggest challenges involve systemic diseases, or diseases affecting the entire body rather than a single organ or body part. For those diseases, super-high doses of gene therapy reagents must be delivered. Such diseases involve not only technical challenges – such as how to manufacture enormous amounts of gene therapy compounds without contaminating them – but also difficulties ensuring that the treatment targets diseased tissues without causing toxic immune side effects. That level of a problem does not exist with the eye, where relatively small doses are used and exposure to the rest of the body is limited.</p>
<p>Another challenge is how to address diseases in which the target gene is very large. Current approaches to delivering treatments into cells lack the capacity to hold large genes.</p>
<p>Cost remains a key issue in this effort – gene therapy drugs are <a href="https://www.nytimes.com/2017/09/11/health/cost-gene-therapy-drugs.html">enormously expensive</a>. As drug manufacturers are able to refine this technique, gene therapy drugs may become more commonplace, causing their price to drop as a result.</p><img src="https://counter.theconversation.com/content/200526/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jean Bennett was a founder of GenSight Biologics and Opus Genetics and was a scientific (non-equity holding) founder of Spark Therapeutics. She and her husband waived any potential financial gain from Luxturna in 2002 so that they could conduct the clinical trials. Her team received funds from the Children's Hospital of Philadelphia, Foundation Fighting Blindness and Spark Therapeutics to run those trials. She is a co-author on a number of gene therapy patents, including one on LCA5 gene therapy that was licensed to Opus Genetics. She also is a co-author of intellectual property relating to use of virtual reality for vision assessment. She also serves on Scientific Advisory Boards for several groups and serves on Boards of two companies (Opus Genetics and REGENXBIO) and a private Foundations (RDFund).</span></em></p>Genetics expert Jean Bennett explains how gene therapy is being used to treat certain forms of inherited blindness.Jean Bennett, Professor Emeritus of Ophthalmology; Cell and Developmental Biology, University of PennsylvaniaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2008032023-04-19T12:47:07Z2023-04-19T12:47:07ZErasing or replacing errors in a patient’s genetic code can treat and cure some genetic diseases<figure><img src="https://images.theconversation.com/files/512982/original/file-20230301-20-1v7gbc.jpg?ixlib=rb-1.1.0&rect=187%2C123%2C1762%2C1212&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Gene editing may hold promise for curing some diseases.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/concept-of-treatment-and-adjustment-of-dna-royalty-free-image/1316503044?phrase=gene%20editing&adppopup=true">Natali_Mis/iStock via Getty Images Plus</a></span></figcaption></figure><p><em>Genetic diseases can have devastating consequences for the people who inherit them. In recent years, scientists have found that there are human genetic diseases that might be treatable, and perhaps even curable, through gene editing. Gene editing is the process by which sections of a person’s DNA are altered. Commonly compared to a word processor or a pencil and eraser, precision gene editing agents can alter sections of a person’s genome to correct “misspellings,” or mutations, in their DNA.</em> </p>
<p><em><a href="https://chemistry.harvard.edu/people/david-r-liu">David Liu</a> is a professor of natural sciences at Harvard University. He co-founded several biotechnology companies including Prime Medicine, Beam Therapeutics, Editas Medicine, Chroma Medicine, Pairwise Plants, Exo Therapeutics, Resonance Medicine, and Nvelop Therapeutics. Liu and his team pioneered <a href="https://doi.org/10.1038/nature17946">base</a> editing and <a href="https://doi.org/10.1038/s41586-019-1711-4">prime</a> editing, two new innovative methods of gene editing that allow for precise alterations to a person’s genetic code.</em></p>
<p><em>In March, Liu’s video was shared with participants at the 2023 <a href="https://www.imaginesolutionsconference.com/">Imagine Solutions Conference</a> in Naples, Florida, about how gene editing works, why it is important, and the strides he and his team have made in the field so far.</em> </p>
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<figcaption><span class="caption">David Liu speaking at the Imagine Solutions 2023 Conference.</span></figcaption>
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<p><strong>What is gene editing, and why are scientists interested in developing and using this tool?</strong></p>
<p><a href="https://www.genome.gov/about-genomics/policy-issues/what-is-Genome-Editing">Gene editing</a> is a technique that makes it possible to purposefully change genes in the <a href="https://medlineplus.gov/genetics/understanding/basics/dna/">DNA</a> of different organisms, including <a href="https://doi.org/10.3390/ijms21165665">crops</a> and <a href="https://doi.org/10.1080/19768354.2020.1726462">animals</a>. Scientists are interested in developing and using genome editors because they are powerful tools for studying biology, treating human diseases and <a href="https://doi.org/10.3389/fsufs.2021.685801">improving agriculture</a>. More than <a href="https://clinicaltrials.gov">50 clinical trials</a> using gene editing to treat a variety of disorders are in progress.</p>
<p>According to the U.S. <a href="https://www.genome.gov/dna-day/15-ways/rare-genetic-diseases">National Human Genome Research Institute</a>, around 280 million individuals worldwide live with a rare genetic disease. Most of these individuals have few to no treatment options, leaving them resigned to their genetic fate.</p>
<p><strong>Can you explain the difference between base and prime editing? Why would scientists use one over the other?</strong></p>
<p>Neither <a href="https://doi.org/10.1038/s41573-020-0084-6">base editors</a> nor <a href="https://doi.org/10.1038/s41434-021-00263-9">prime editors</a> exist in nature; instead, both were engineered in our laboratory from natural and laboratory-evolved components. </p>
<p><a href="https://doi.org/10.1038/nature17946">Base editing</a>, often compared to a pencil and eraser, can precisely and efficiently correct <a href="https://doi.org/10.1038/nature24644">four of the most common types of misspellings</a> that occur in DNA, together accounting for about 30% of all known disease-causing DNA errors. Base editors perform a chemical reaction on an individual DNA letter, or “base,” rearranging its atoms to instead become a different DNA base. But base editing cannot be used to correct mistakes such as extra letters, missing letters or the remaining types of single-letter misspellings in DNA. </p>
<p>In contrast, <a href="https://doi.org/10.1038/s41586-019-1711-4">prime editors</a>, sometimes compared to the “search and replace” feature in a word processor, can replace any stretch of up to hundreds of DNA letters with virtually any other sequence of letters. In theory, the versatility of prime editing makes it possible to correct most known DNA misspellings that cause disease by restoring the typical DNA sequence. </p>
<p>Base editing and prime editing each have their own strengths and weaknesses. Whether a scientist should use base or prime editing depends on numerous factors such as the specific sequence being edited, its unique sequence context, whether the edit will be made inside an animal or patient, and the specific goals of the scientist. </p>
<p><strong>How can gene editing treat disease?</strong></p>
<p>The words “bean” and “been” differ by only a single letter, yet they have completely different meanings. In a cellular context, a single-letter misspelling in a specific position in a person’s DNA – for example, from a C to a T – can mean the difference between a healthy individual and an individual with progeria, a rare genetic disease that causes children to age rapidly. Base editing has the potential to correct these small but critical DNA misspellings to reverse or cure disease.</p>
<p><a href="https://doi.org/10.1038/s41586-020-03086-7">In a 2021 study</a> that our lab conducted in collaboration with scientists at the National Institutes of Health and Vanderbilt University, we used base editing to reverse progeria in mice and more than doubled their life span. In the same year, we used base editing to convert a diseased form of the hemoglobin gene <em>HBB</em> to a benign variant to <a href="https://doi.org/10.1038/s41586-021-03609-w">treat sickle-cell disease in mice</a>. </p>
<p>Base editing has also been successfully used in humans. After treatments of chemotherapy and a bone marrow transplant failed to treat 13-year-old <a href="https://www.bbc.com/news/health-63859184">Alyssa’s</a> pediatric leukemia, she enrolled in a <a href="https://www.isrctn.com/ISRCTN15323014">clinical trial</a> led by <a href="https://www.waseemqasim.com/">Waseem Qasim’s team</a> at the University of College London. The base-edited T-cells cleared Alyssa’s cancer and she remains in complete remission seven months later. </p>
<p><strong>What implications does prime editing have for the study and treatment of genetic disease and human health?</strong></p>
<p>Much like base editing, <a href="https://doi.org/10.1016/j.tcb.2020.01.004">prime editing</a> has tremendous implications for studying and treating genetic diseases. Because of its unique ability to make virtually any localized change in DNA at a target sequence, prime editing has the potential to correct a much larger number of mutations that are known to cause genetic diseases than was previously possible. Before prime editors can be used routinely to treat genetic diseases, however, they must be tested for their safety and efficacy in patients, and for their compatibility with different delivery platforms.</p>
<p>Additionally, the therapeutic application of any genome editing technology requires a clear understanding of the relationship between the genetic mutation and the resulting disease to ensure that the benefits outweigh the risks. </p>
<p><strong>What recent or ongoing development are you most excited about in your field?</strong></p>
<p>I am excited that many labs, including <a href="https://www.liugroup.us/">my own</a>, are <a href="https://doi.org/10.1126/science.aax9181">developing methods</a> <a href="https://doi.org/10.1038/s41587-021-01133-w">to precisely</a> <a href="https://doi.org/10.1038/s41587-021-01133-w">install</a> entire healthy genes into specific positions in the human genome. This could expand the potential therapeutic reach of gene editing. </p>
<p>I’m also excited about <a href="https://doi.org/10.1038/s41392-019-0089-y">ongoing efforts</a> to develop delivery technologies that can safely and efficiently deliver genome editing agents into target cells in animals and human patients. Genome editing agents are unable to easily enter cells because of their large size, unlike <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/small-molecule-drug">small-molecule drugs</a> like ibuprofen and aspirin which can easily enter cells due to their low molecular weight. As a result, scientists have to use creative ways to deliver genome editors to their targets — a critical step if we hope to broaden the scope of therapeutic gene editing.</p>
<p>To this end, we recently developed <a href="https://doi.org/10.1016/j.cell.2021.12.021">engineered viruslike particles</a>, which are capable of delivering base editors and prime editors into specific tissues in living organisms. As the field continues to develop and improve delivery methods, the promise of therapeutic genome editing will continue to include more patient communities.</p>
<p><strong>What ethical aspects of this technology have you and other researchers considered?</strong></p>
<p>There are several ethical issues surrounding the technology that researchers in the field <a href="https://www.nature.com/articles/d41586-019-00726-5">have considered</a>, including the challenges of <a href="https://doi.org/10.1038/s41587-021-01191-0">achieving equitable access</a> to genome editing technologies, the <a href="https://doi.org/10.1089/crispr.2021.0053">potential for increased stigmatization</a> of marginalized individuals and the <a href="https://doi.org/10.1007/s13238-017-0477-4">potential for misuse</a>. In cases where the technology is used with good intent, such as to treat disease and alleviate suffering, questions of <a href="https://doi.org/10.1016/j.ymthe.2016.12.012">patient accessibility</a> become paramount.</p>
<p>No fundamental technology is inherently good or bad, and the ability to edit our genomes is no exception. My hope continues to be that we collectively and thoughtfully choose to use these powerful technologies for the betterment of as many people as possible.</p><img src="https://counter.theconversation.com/content/200803/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>DRL is a co-founder and consultant for Beam Therapeutics, Prime Medicine, Pairwise Plants, Exo Therapeutics, Chroma Medicine, Resonance Medicine, and Nvelop Therapeutics. He owns founders’ equity in these companies, receives consultancies from them, and serves on their scientific advisory boards. He also serves as a scientific advisory board member and equity owner of Tevard Biosciences and Insitro. DRL may receive honoraria and travel reimbursements for some speaking engagements. He is a co-inventor on patents related to his research, as listed on his CV at <a href="http://liugroup.us">http://liugroup.us</a>. Some of these patents have been licensed to companies including those listed above. Potential conflicts of interest between his academic activities and his activities with other entities including the companies above are actively disclosed and managed in accordance with the conflict of interest policies of the Broad Institute, Harvard University, and HHMI.
The policies are available at:
<a href="https://www.broadinstitute.org/administration/conflict-interest-policy">https://www.broadinstitute.org/administration/conflict-interest-policy</a>
<a href="https://vpr.harvard.edu/pages/financial-conflict-interest-policy">https://vpr.harvard.edu/pages/financial-conflict-interest-policy</a>
<a href="https://www.hhmi.org/about/policies">https://www.hhmi.org/about/policies</a></span></em></p>Chemist David Liu explains how gene editing is paving the way to treating and even curing certain genetic diseases.David Liu, Professor of the Natural Sciences at Harvard University, Harvard UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2012342023-03-10T22:42:38Z2023-03-10T22:42:38ZSomatic genome editing therapies are becoming a reality – but debate over ethics, equitable access and governance continue<figure><img src="https://images.theconversation.com/files/514625/original/file-20230310-30-d4sd7f.jpg?ixlib=rb-1.1.0&rect=0%2C51%2C5760%2C3181&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Sangharsh Lohakare / Unsplash</span></span></figcaption></figure><p>Hundreds of experts from around the world gathered at the Francis Crick Institute in London this week for the Third International Summit on Human Genome Editing.</p>
<p>As at the first and second summits, held in Washington DC in 2015 and Hong Kong in 2018, leading experts in research shared their discoveries and discussed how they should be used. </p>
<p>The prospect of curing certain diseases by changing the parts of our DNA that cause them is becoming a reality. A somatic genome editing treatment for sickle cell disease is set to obtain <a href="https://www.barrons.com/articles/crispr-therapeutics-stock-fda-sickle-cell-gene-therapy-bf56a18c">regulatory approval</a> in the US later this year.</p>
<p>“Delivery” was a recurring issue: the delivery of equitable access to genome editing therapies, ongoing research to optimise delivery systems for genome editing apparatus and delivery of measures to foster discussions regarding regulation, governance, public and patient engagement.</p>
<p>American Nobel laureate David Baltimore aptly noted in his opening remarks, “new technologies continue to challenge our society”. The advent of CRISPR gene-editing technology, short for “Clustered Regularly Interspaced Short Palindromic Repeats”, has reaffirmed this proposition, igniting a global dialogue on its accompanying ethical and regulatory issues. </p>
<p>Five years after the last summit, CRISPR technology has continued to mature. It is an insurmountable task to capture all of the developments in both the science and ethics of CRISPR technology. These will be addressed with reference to the key themes raised during the summit – scientific developments, accessibility and the importance of public and patient engagement. </p>
<h2>Scientific developments</h2>
<p>Many new advances in genome editing techniques were presented. </p>
<p>American chemist and biologist David Liu reported on findings to use “<a href="https://www.nature.com/articles/d41587-019-00032-5">prime editing</a>” to treat genetic conditions such as Huntington’s disease and Friedreich’s ataxia. Unlike CRISPR, which makes a double stranded cut in the DNA, prime editing induces a single stranded cut. This makes it more versatile and precise for targeted deletion and insertion of genetic sequences.</p>
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Read more:
<a href="https://theconversation.com/what-is-gene-editing-and-how-could-it-shape-our-future-199025">What is gene editing and how could it shape our future?</a>
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<p>The summit heard about Vertex Pharmaceutical’s CRISPR-based treatment for sickle cell disease. The treatment is <a href="https://www.statnews.com/2023/03/07/crispr-sickle-cell-access/">expected</a> to become the first approved CRISPR genome editing therapy later this year.</p>
<p>There were also reports of research using CRISPR technology to treat diseases including Duchenne muscular dystrophy, cancer, HIV/AIDS, heart and muscle disease and inborn errors of immunity. American molecular biologist Eric Olson reported success in using base editing to <a href="https://www.science.org/doi/10.1126/science.ade1105">target CaMKIIδ</a>, a central regulator of cardiac signalling, in restoring cardiac function, as a treatment for myocardial infarction. </p>
<h2>Equitable access</h2>
<p>As research proceeds and treatments become available, questions about equitable access to the technology arise.</p>
<p>Equity extends beyond considerations of cost, access and ownership, to research engagement and output. This refers to capacity for knowledge production, data sovereignty and collection, access to latest knowledge, opportunities for collaboration and infrastructure to facilitate recruitment and trialling of new therapies. </p>
<p>Access issues are particularly relevant to lower- and middle-income countries, which may be compromised by systemic and structural inequities. Policy and political landscapes, economic constraints and scientific racism further perpetuate this inequity. </p>
<p>Gautam Dongre, representing the National Alliance of Sickle Cell Organisations India, described the reality of those living with sickle cell disease in India, where access to treatment is dire: </p>
<blockquote>
<p>“Our priority is to be alive, to receive gene therapy in the future.”</p>
</blockquote>
<h2>Patient perspectives and public engagement</h2>
<p>The summit also gave a platform to the experiences and concerns of people with lived experience of genetic disease. This included insights into the role and utility of public engagement, such as patient advocacy groups, do-it-yourself community groups and citizens’ juries.</p>
<p>A memorable presentation from Victoria Gray – the first recipient of Vertex Pharmaceutical’s CRISPR therapy for sickle cell disease – highlighted its life-changing impact. Gray says her CRISPR-modified “super cells” have cured her, enabling her to lead a disease-free life. The great potential of CRISPR technology can be realised, but importantly, it must be accessible to all.</p>
<h2>Concluding remarks</h2>
<p>How should CRISPR technology be regulated? This is a critical question.</p>
<p>As the summit’s organisers <a href="https://royalsociety.org/-/media/events/2023/03/human-genome-editing-summit/statement-from-the-organising-committee-of-the-third-international-summit-on-human-genome-editing.pdf">noted</a>, somatic genome editing has made “remarkable progress”, demonstrating its capability to “cure once-incurable diseases”. Further research is needed to target more diseases and enhance our understanding of risks and unintended consequences.</p>
<p>“Somatic” genome editing (which makes changes that are not heritable) is different to germline and heritable genome editing (which makes heritable changes). </p>
<p>Basic research for germline genome editing, which is not for reproduction purposes, is underway, for example, in gametes and embryos to explore aspects of early development. However, the organising committee concluded that heritable human genome editing for reproduction purposes “remains unacceptable at this time”. This is in light of the absence of preclinical evidence for safety and efficacy, legal authorisation and rigorous oversight and governance.</p>
<p>The concept of “safe enough” was interrogated – whose ethics should be applied to make this value judgment? Does the notion of safety traverse into areas beyond medically defined risks of physical harm? </p>
<p>It is notable that risk tolerance and perception of safety is dictated by an individual’s position in their country, culture, socio-economic status and lived experience. </p>
<p>In 2021, the World Health Organization published <a href="https://www.who.int/publications/i/item/9789240030060">a framework for governing human genome editing</a>. This retains its authority as an exemplar for a pathway toward an appropriate regulatory framework. While not overly prescriptive, it was designed to be adaptable for implementation in any jurisdiction. This year, Uganda plans to implement the framework as a pilot project. </p>
<p>The organising committee called for global action to explore measures for equitable and affordable pathways to access genome editing therapies. Ongoing global discussions are far from complete, and perhaps may never be complete, reinforcing the need for collective dialogue to proceed this summit. <em>And on with research, innovation and collaboration</em>.</p><img src="https://counter.theconversation.com/content/201234/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Olga C. Pandos is a recipient of the Australian Government Research Training Program Scholarship.</span></em></p>At the Third International Summit on Human Genome Editing, experts gather to discuss the path forward for CRISPR and other gene-editing technologiesOlga C. Pandos, PhD Candidate in Technology, Medical Law and Ethics, University of AdelaideLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1938192022-11-07T12:34:36Z2022-11-07T12:34:36ZEpilepsy: gene therapy technique targeting overactive brain cells shows promise in treating drug-resistant form of the condition<figure><img src="https://images.theconversation.com/files/493789/original/file-20221107-13-i4n7qr.jpg?ixlib=rb-1.1.0&rect=26%2C0%2C3500%2C1996&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Epileptic seizures are caused by brain cells becoming overactive.
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/neuronal-network-electrical-activity-neuron-cells-1691666992">MattLphotography/ Shutterstock</a></span></figcaption></figure><p>Something like <a href="https://www.who.int/news-room/fact-sheets/detail/epilepsy">50 million people worldwide</a> have epilepsy. While the majority of these people are able to use medications to manage and prevent their seizures, around one-third don’t respond well to these treatments. In such cases, the only option available to bring seizures under control is to <a href="https://epilepsysociety.org.uk/about-epilepsy/treatment/epilepsy-and-brain-surgery">remove the part of the brain</a> where seizures arise. But this procedure is extremely risky.</p>
<p>Since epileptic seizures are caused by excessive activity of brain cells (neurons) in specific parts of the brain, being able to target these neurons and turn them off could very well prevent seizures from happening.</p>
<p>Using an innovative new gene therapy approach we have developed, we were able to show in cell and animal models that it is possible to <a href="https://www.science.org/doi/epdf/10.1126/science.abq6656">specifically target the neurons</a> that cause epileptic seizures. This subsequently prevented them from becoming overactive and causing seizures in the future. </p>
<p>This discovery not only has major implications for treating drug-resistant epilepsy, but there’s a chance it may also be used to treat other neurological conditions caused by overactive neurons, including Parkinson’s disease and migraines.</p>
<h2>Gene therapy</h2>
<p>Gene therapy works by directly altering a person’s genes in order to treat a disease or condition. There are a few different ways of doing this.</p>
<p><a href="https://www.jneurosci.org/content/early/2019/02/12/JNEUROSCI.1143-18.2019?versioned=true">Previous studies</a> that have used gene therapy to treat epilepsy in animal models have done this by using a virus that has been altered in the lab so it’s no longer harmful. Researchers would inject the virus into the brain region where seizures occur. The virus would then implant stretches of DNA into the cells, effectively modulating the way they worked – <a href="https://www.nature.com/articles/s41591-018-0103-x">making them less active</a> and preventing seizures.</p>
<p>While this technique is far less invasive than brain surgery, the problem with the method is that it affects all the neurons in the brain region – not just those causing the seizures. It also permanently alters the properties of the cells that take up the virally delivered DNA, which can permanently modify brain function. </p>
<p>But our innovative new gene therapy tool has shown it’s possible to alter only the brain cells that cause seizures, leaving nearby healthy neurons unaffected. We were able to do this by taking advantage of how gene expression is normally regulated.</p>
<figure class="align-center ">
<img alt="An image of multiple DNA strands." src="https://images.theconversation.com/files/493795/original/file-20221107-3705-r3aoea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/493795/original/file-20221107-3705-r3aoea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/493795/original/file-20221107-3705-r3aoea.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/493795/original/file-20221107-3705-r3aoea.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/493795/original/file-20221107-3705-r3aoea.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/493795/original/file-20221107-3705-r3aoea.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/493795/original/file-20221107-3705-r3aoea.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Our new gene therapy tool targeted the body’s promoters.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/dna-molecule-macro-blue-string-on-775854724">SynthEx/ Shutterstock</a></span>
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<h2>The role of promoters</h2>
<p>The 20,000 or so genes we have in our body each contain instructions to make different proteins and molecules. These genes are typically under the control of neighbouring stretches of DNA, called promoters. These determine whether and how much of a particular protein is made. Different cells express different proteins depending on which promoters are active or inactive.</p>
<p>There’s also a special type of promoter (called “activity-dependent” promoters) that will only switch on in response to biochemical signals made by neurons when they fire intensely – such as during a seizure. We took advantage of these activity-dependent promoters, creating a gene therapy that senses and turns down the excitability of neurons that cause seizures. We did this by coupling activity-dependent promoters to DNA sequences that contain proteins which calm down neurons.</p>
<p>We initially tested the gene therapy tool in neurons grown in a dish, and then in mice that had drug-resistant epilepsy. We also tested this technique in lab-grown human “mini brains”. </p>
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<p>
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<strong>
Read more:
<a href="https://theconversation.com/scientists-grow-brain-tissue-with-different-regions-in-lab-17560">Scientists grow brain tissue with different regions in lab</a>
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</em>
</p>
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<p>In each test, we were able to show this new gene therapy technique was effective in calming down the overactive neurons involved in seizures, while leaving healthy bystander cells unaffected.</p>
<p>Although it takes an hour or so to switch on – longer than the typical duration of a seizure – the new gene therapy is highly effective in preventing subsequent seizures. It does this by automatically selecting which neurons to treat and switching them off. It’s also able to return neurons to their original state when brain activity returns to normal. If seizures occur again, the promoter is ready to switch on. </p>
<p>The treatment therefore only has to be given once, but has a lasting effect – possibly lifelong. Importantly, the treatment did not affect the performance of the mice in tests of memory and other normal behaviour (such as their anxiety levels, learning and mobility).</p>
<p>We are excited by the breakthrough, because it could in principle bring the prospect of gene therapy to a wide range of people with drug-resistant epilepsy. But before the therapy is ready to use with these patients, we will need to put it through a number of tests to verify that it can be scaled up to larger brains.</p><img src="https://counter.theconversation.com/content/193819/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gabriele Lignani consults to/owns shares in a company that aims to bring epilepsy gene therapy to the clinic. He received funding from Epilepsy Research UK and Medical Research Council. </span></em></p><p class="fine-print"><em><span>Dimitri Kullmann consults to/owns shares in a company that aims to bring epilepsy gene therapy to the clinic. He received funding from the Wellcome Trust and the Medical Research Council.</span></em></p>This technique could also be applied to other conditions, such as Parkinson’s disease.Gabriele Lignani, Associate Professor, Clinical & Experimental Epilepsy, UCLDimitri Kullmann, Professor of Neurology, UCLLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1875152022-08-01T12:27:02Z2022-08-01T12:27:02ZHelping cells become better protein factories could improve gene therapies and other treatments – a new technique shows how<figure><img src="https://images.theconversation.com/files/476727/original/file-20220729-13650-l4tehb.jpg?ixlib=rb-1.1.0&rect=5%2C0%2C1991%2C1500&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Your genetic material instructs your cells to produce the proteins encoded in it.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/protein-synthesis-illustration-royalty-free-illustration/1296294290">Juan Gaertner/Science Photo Library via Getty Images</a></span></figcaption></figure><p>The cells in your body are <a href="https://www.ncbi.nlm.nih.gov/books/NBK26885/">not all the same</a>. Each of your organs has cells with very different functions. For example, liver cells are top-notch secretors, as their job requires them to make and export many of the proteins in your blood. By contrast, muscle cells are tasked with facilitating the contractions that allow you to move. </p>
<p>The fact that cells are so specialized has implications for <a href="https://medlineplus.gov/genetics/understanding/therapy/procedures/">gene therapy</a>, a way to treat genetic diseases by correcting the source of the error in a patient’s DNA. Health providers use a harmless <a href="https://patienteducation.asgct.org/gene-therapy-101/vectors-101">viral or bacterial vector</a> to carry a corrective gene into a patient’s cells, where the gene then directs the cell to produce the proteins necessary to treat the disease. Muscle cells are a common target because gene therapies <a href="https://medlineplus.gov/genetics/understanding/therapy/procedures/">injected into the muscle</a> are more accessible than introduction into the body by other routes. But muscle cells may not produce the desired protein as efficiently as needed if the job the gene instructs it to do is very different from the one it specializes in.</p>
<p>We are <a href="https://scholar.google.com/citations?user=SPyKrnIAAAAJ&hl=en">cell biologists</a> and <a href="https://scholar.google.com/citations?user=PL6N9eoAAAAJ&hl=en">biophysicists</a> who study how healthy proteins are produced and maintained in cells. This field is called <a href="https://doi.org/10.1093%2Fgerona%2Fgln071">protein homeostasis, also known as proteostasis</a>. Our <a href="https://dx.doi.org/10.1073/pnas.2206103119">recently published study</a> details a way to make muscle cells behave more like liver cells by changing protein regulation networks, enhancing their ability to respond to gene therapy and treat genetic diseases.</p>
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<figcaption><span class="caption">Gene therapy involves replacing a defective gene with a functioning one that can direct cells to produce missing or dysfunctional proteins.</span></figcaption>
</figure>
<h2>Boosting protein factories</h2>
<p>One disease for which gene therapy has great potential is <a href="http://doi.org/10.1056/NEJMra1910234">alpha-1 antitrypsin (AAT) deficiency</a>, a condition in which liver cells are unable to make adequate amounts of the protein AAT. It results in a breakdown of lung tissue that can cause <a href="https://www.uncoveralpha1.com/what-is-alpha-1">serious respiratory problems</a>, including the development of severe lung diseases such as chronic obstructive pulmonary disease (COPD) or emphysema. </p>
<p>Patients are usually treated by <a href="https://www.nhlbi.nih.gov/health/alpha-1-antitrypsin-deficiency">receiving AAT via infusion</a>. But this requires patients to either make regular trips to the hospital or keep expensive equipment at home for the rest of their lives. Replacing the faulty gene that caused their AAT shortage in the first place could be a boon for patients. Current gene therapies inject the AAT-producing gene into muscle. One of our colleagues, <a href="https://scholar.google.com/citations?user=Sd6B6-UAAAAJ&hl=en">Terence Flotte</a>, developed a way to use a harmless version of an adeno-associated virus as a vehicle to deliver AAT gene therapies into the body via injection, allowing for <a href="https://doi.org/10.1016/j.ymthe.2017.03.029">sustained release of the protein</a> over several years.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of panlobular emphysema" src="https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=404&fit=crop&dpr=1 600w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=404&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=404&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=507&fit=crop&dpr=1 754w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=507&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/476729/original/file-20220729-13356-h2dp31.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=507&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Lung damage from alpha-1 antitrypsin deficiency can lead to emphysema.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/8TqvpQ">Atlas of Pulmonary Pathology/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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<p>But muscle cells aren’t very good at producing the AAT proteins the gene instructs them to make. Flotte and his team found that AAT levels one to five years after gene therapy were <a href="https://doi.org/10.1016/j.ymthe.2017.03.029">only 2% to 2.5%</a> of the optimal concentration for therapeutic effect.</p>
<p>We wanted to find a way to turn muscle cells into better protein factories, like liver cells. We tested a number of different molecules on mice muscle cells to determine if they would boost AAT secretion. We found that adding a molecule called <a href="https://doi.org/10.1074/jbc.M112.404707">suberoylanilide hydroxamic acid, or SAHA</a>, helps muscle cells make AAT at a production level more like that of liver cells. It works because SAHA is a <a href="https://doi.org/10.7554%2FeLife.15550">proteostasis regulator</a> with the ability to boost the cell’s protein output.</p>
<p>Down the road, we believe that adding SAHA or similar proteostasis regulators to gene therapies could help increase the effectiveness of these treatments for many genetic diseases.</p>
<h2>Beyond gene therapy</h2>
<p>Our findings have implications beyond just gene therapies. The effectiveness of <a href="https://doi.org/10.1038/s41573-021-00283-5">mRNA vaccines</a>, for example, is also affected by how well each cell produces a particular type of protein. Because most mRNA vaccines are given through an injection to the muscle, they may also face the same limitations as gene therapies and produce a lower-than-desirable immune response. Increasing the protein production of muscle cells could potentially improve vaccine immunity.</p>
<p>Additionally, many drugs created by the biotech industry called <a href="https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers">biologics</a> that are derived from natural sources rely heavily on a given cell’s <a href="https://doi.org/10.3389/fbioe.2019.00420">protein production capabilities</a>. But many of these drugs use <a href="https://weekly.biotechprimer.com/biomanufacturing-how-biologics-are-made/">cells that aren’t specialized to make large amounts of protein</a>. Adding a protein homeostasis enhancer to the cell could optimize protein yield and increase the effectiveness of the drug.</p>
<p>Protein homeostasis is a burgeoning field that goes beyond drug development. Many <a href="https://doi.org/10.1038/s41580-019-0101-y">neurodegenerative diseases</a> like Alzheimer’s and Parkinson’s are linked to abnormal protein regulation. The deterioration of a cell’s ability to manage protein production and use over time may contribute to age-related diseases. Further research on ways to improve the cellular machinery behind protein homeostasis could help delay aging and open many new doors for treating a wide range of diseases.</p><img src="https://counter.theconversation.com/content/187515/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Daniel N. Hebert receives funding from Alpha One Foundation and NIH/NIGMS. </span></em></p><p class="fine-print"><em><span>Lila Gierasch receives funding from NIH/NIGMS and the Alpha1 Foundation.</span></em></p>Gene therapies and vaccines are often injected into muscle cells that are inefficient at producing desired proteins. Making them work more like liver cells could lead to better treatment outcomes.Daniel N. Hebert, Professor of Biochemistry and Molecular Biology, UMass AmherstLila Gierasch, Distinguished Professor of Biochemistry and Molecular Biology, UMass AmherstLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1768702022-02-14T13:21:37Z2022-02-14T13:21:37ZFirst gene therapy for Tay-Sachs disease successfully given to two children<figure><img src="https://images.theconversation.com/files/446010/original/file-20220211-13-1kn2g6a.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2049%2C1463&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">About 1 in 300 people in the general population carry the Tay-Sachs disease gene.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/baby-boy-on-mothers-lap-royalty-free-image/800441978">Ray Kachatorian/Stone via Getty Images</a></span></figcaption></figure><p>Two babies have received the <a href="https://doi.org/10.1038/s41591-021-01664-4">first-ever gene therapy</a> for Tay-Sachs disease after over 14 years of development.</p>
<p><a href="https://medlineplus.gov/genetics/condition/tay-sachs-disease/">Tay-Sachs</a> is a severe neurological disease caused by a deficiency in an enzyme called HexA. This enzyme breaks down a fatlike substance that normally exists in very small, harmless amounts in the brain. Without HexA, however, this fatlike substance can accumulate to toxic levels that damage and kill neurons. </p>
<p>One of the symptoms of this disease was first described in 1883 by British ophthalmologist <a href="https://embryo.asu.edu/pages/warren-tay-1843-1927">Warren Tay</a>, who saw a cherry-red spot on the back of the eye of affected infants. In 1887, American neurologist <a href="https://doi.org/10.1097%2F00005053-188714090-00001">Bernard Sachs</a> described the profound neurological symptoms of Tay-Sachs in a seminal paper:</p>
<blockquote>
<p>“… Nothing abnormal was noticed until the age of two to three months, when the parents observed that the child was much more listless than children of that age. … The child would ordinarily lay upon its back, and was never able to change its position … it never attempted any voluntary movement … the child grew steadily weaker, it ceased to take its food properly, its bronchial troubles increased, and finally, pneumonia set in, it died August, 1886.”</p>
</blockquote>
<p>This dismal description of Tay-Sachs <a href="https://rarediseases.org/rare-diseases/tay-sachs-disease/">remains current</a>, and those with the disease usually die by age 5. Some people develop Tay-Sachs later in life, with symptoms starting in their teens that get progressively worse over many decades.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/445732/original/file-20220210-40846-10w6ivu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration of a cherry-red spot on the retina of someone with Tay-Sachs" src="https://images.theconversation.com/files/445732/original/file-20220210-40846-10w6ivu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/445732/original/file-20220210-40846-10w6ivu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/445732/original/file-20220210-40846-10w6ivu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/445732/original/file-20220210-40846-10w6ivu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/445732/original/file-20220210-40846-10w6ivu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/445732/original/file-20220210-40846-10w6ivu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/445732/original/file-20220210-40846-10w6ivu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Patients with Tay-Sachs often have a cherry-red spot in the retina of their eyes.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/eye-retina-in-tay-sachs-disease-illustration-royalty-free-image/1359398669">Kateryna Kon/Science Photo Library via Getty Images</a></span>
</figcaption>
</figure>
<p>Unfortunately there is still no treatment for Tay-Sachs. Aggressive medical treatment can extend survival but doesn’t improve neurological function. The only effective way to treat Tay-Sachs is to restore the HexA enzyme in the brain. This is difficult, however, because the <a href="https://rarediseases.org/rare-diseases/tay-sachs-disease/">blood-brain barrier</a> prevents most molecules from passing into the brain.</p>
<p><a href="https://www.researchgate.net/profile/Miguel-Sena-Esteves">I am</a> a member of a team of researchers from UMass Chan Medical School and Auburn University who developed a gene therapy that may help get around this barrier. Our treatment uses two harmless viral vectors to deliver DNA instructions to brain cells that teach them how to produce the missing enzyme. <a href="https://doi.org/10.1038/d41573-021-00017-7">Similar techniques</a> have been used to treat a number of <a href="https://rarediseases.org/rare-diseases/lysosomal-storage-disorders/">related diseases</a> and other conditions. In the case of Tay-Sachs, these DNA instructions enter the nucleus of these cells and stay there, allowing for long-term production of HexA. Based on our previous studies successfully testing our gene therapy on <a href="https://doi.org/10.1016/j.ymthe.2020.06.021">different</a> <a href="https://doi.org/10.1038/gt.2014.108">animal</a> <a href="https://doi.org/10.1089/hum.2017.163">species</a>, we believe that delivering the treatment to a central part of the brain allows the enzyme to travel along its connections to other regions and to be distributed throughout the entire brain.</p>
<p>The first child who received our gene therapy treatment was age 2 ½, with late-stage disease symptoms. Three months after treatment, they had better muscle control and could focus their eyes. Now at age 5, the child is in stable health and is seizure-free, which usually isn’t possible for patients at this age. A second child treated at age 7 months had improved brain development by the three-month follow-up and remains seizure-free at a little over age 2. </p>
<p>More testing is needed to confirm whether our treatment can fully stop disease progression. Given that this was the first time our treatment was given to humans, we used a conservative dose below the maximum therapeutic effects we saw in our animal studies. My colleagues and I are currently conducting a follow-up clinical trial to test the safety and efficacy of increasing doses in a larger number of patients.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/e3jlXm6CLns?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Researching rare diseases can lead to advances in medicine as a whole.</span></figcaption>
</figure>
<p>The <a href="https://doi.org/10.1016/j.xphs.2021.03.024">increasing cost</a> of manufacturing these treatments makes it extremely difficult, if not impossible, to develop and test gene therapy for many ultrarare diseases where the number of patients worldwide is very small and <a href="https://www.forbes.com/sites/clairenovorol/2020/02/28/the-challenges-of-combating-rare-diseasesand-five-innovations-making-a-real-difference/?sh=2ece2a1235a5">profitability low</a>.</p>
<p>We were able to deliver these treatments to the children in our ongoing clinical trials thanks only to funding from a generous family whose own child is a participant. This grassroots approach is a <a href="https://www.statnews.com/2017/06/30/rare-disease-crowdfund-purnell/">common theme</a> in ultrarare disease research – development and testing are often supported by parents, foundations and federal grants.</p>
<p>Our <a href="https://www.umassmed.edu/translational-institute-for-molecular-therapeutics/">Translational Institute for Molecular Therapeutics</a> program at UMass Chan Medical School focuses on developing more viral vector gene therapies for an ever-expanding number of ultrarare diseases in collaboration with families and foundations. We believe every patient afflicted with any of the approximately <a href="https://dx.doi.org/10.1038%2Fd41573-019-00180-y">7,000 rare diseases</a> worldwide deserves a chance at a normal life.</p>
<p>[<em><a href="https://memberservices.theconversation.com/newsletters?nl=science&source=inline-science-corona-important">Get The Conversation’s most important coronavirus headlines, weekly in a science newsletter</a></em>]</p><img src="https://counter.theconversation.com/content/176870/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Miguel Sena-Esteves received funding from several foundations (National Tay-Sachs and Allied Disease Association, Cure Tay-Sachs Foundation, and the BluGenes Foundation) and the National Institutes of Health during development of the AAV gene therapy for Tay-Sachs disease</span></em></p>Tay-Sachs is a rare and fatal neurodegerative disorder that most commonly affects children. Researchers have developed the first Tay-Sachs treatment to reach clinical trials.Miguel Sena-Esteves, Associate Professor of Neurology, UMass Chan Medical SchoolLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1707722022-01-24T13:31:35Z2022-01-24T13:31:35ZHow mRNA and DNA vaccines could soon treat cancers, HIV, autoimmune disorders and genetic diseases<figure><img src="https://images.theconversation.com/files/441838/original/file-20220120-9603-u5kjhi.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C3840%2C2160&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Nucleic acid vaccines use mRNA to give cells instructions on how to produce a desired protein.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/messenger-rna-or-mrna-strand-3d-rendering-royalty-free-image/1295693748?adppopup=true">Libre de Droit/iStock via Getty Images</a></span></figcaption></figure><p><em>The two most successful coronavirus vaccines developed in the U.S. – the Pfizer and Moderna vaccines – are both mRNA vaccines. The idea of using genetic material to produce an immune response has opened up a world of research and potential medical uses far out of reach of traditional vaccines. <a href="https://scholar.google.com/citations?user=eNprtJEAAAAJ&hl=en&oi=ao">Deborah Fuller is a microbiologist</a> at the University of Washington who has been studying genetic vaccines for more than 20 years. We spoke to her about the <a href="https://theconversation.com/mrna-vaccines-asteroid-missions-and-collaborative-robots-what-to-watch-in-science-in-2022-podcast-174413">future of mRNA vaccines for The Conversation Weekly podcast</a>.</em> </p>
<p><em>Below are excerpts from that conversation which have been edited for length and clarity.</em> </p>
<h2>How long have gene-based vaccines been in development?</h2>
<p>This type of vaccine has been in the works for <a href="https://doi.org/10.1038/356152a0">about 30 years</a>. Nucleic acid vaccines are based on the idea that DNA makes RNA and then RNA makes proteins. For any given protein, once we know the genetic sequence or code, we can design an mRNA or DNA molecule that prompts a person’s cells to start making it. </p>
<p>When we first thought about this idea of putting a genetic code into somebody’s cells, we were studying both DNA and RNA. The mRNA vaccines did not work very well at first. They <a href="https://www.nature.com/articles/nrd.2017.243">were unstable</a> and they caused pretty strong immune responses that were <a href="https://doi.org/10.1038/nrd.2017.243">not necessarily desirable</a>. For a very long time DNA vaccines took the front seat, and the very <a href="https://dx.doi.org/10.1038%2Fnrg2432">first clinical trials were with a DNA vaccine</a>.</p>
<p>But about seven or eight years ago, mRNA vaccines started to take the lead. Researchers solved a lot of the problems – notably the <a href="https://doi.org/10.1038/mt.2008.200">instability</a> – and discovered <a href="https://doi.org/10.1073/pnas.1209367109">new technologies to deliver mRNA</a> into cells and ways of modifying the coding sequence to <a href="https://doi.org/10.1038/nrd.2017.243">make the vaccines a lot more safe to use in humans</a>.</p>
<p>Once those problems were solved, the technology was really poised to become a revolutionary tool for medicine. This was just when COVID-19 hit. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A scanning electron microscope image of blue lumpy sphere of a T cell." src="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">DNA and mRNA vaccines are much better at producing T cells than are normal vaccines.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/niaid/5950870236/in/photolist-2mEvEdt-a4RLoY-2mEn5zV-bo51Vz-MSuhWU-bo5rrZ-2kLN4tU-2kLN4uF-SjQFf7-2ewYf1r-rx2LVN-su1wdR-2j4icVg-2iKmbjG-2mfURRa-a7RGBX-xvJ8TV-2hVm2XZ-2hVhUoD-2iKjyJj-51svu9-51ojDi-51sByA-ni2rkv-2iKgNob-Fwbp7g-EpF3rg-HKERqY-51sBff-51ojop-2mfSkUp-2mfMhmB-2mfLV8V-2mfQZZp-2mfLTAG-2mfVWsD-2mfRRSs-2mfQJMF-2mfUQ1m-2mfSjPU">NIAID/NIH via Flickr</a></span>
</figcaption>
</figure>
<h2>What makes nucleic acid vaccines different from traditional vaccines?</h2>
<p>Most vaccines induce antibody responses. Antibodies are the primary immune mechanism that blocks infections. As we began to study nucleic acid vaccines, we discovered that because these vaccines are expressed within our cells, they were also <a href="https://www.gavi.org/vaccineswork/what-are-nucleic-acid-vaccines-and-how-could-they-be-used-against-covid-19#:%7E:text=Nucleic%20acid%20vaccines%20use%20genetic,immune%20response%20against%20it">very effective at inducing a T cell response</a>. This discovery really prompted additional thinking about how researchers could use nucleic acid vaccines not just for infectious diseases, but also for immunotherapy to treat cancers and chronic infectious diseases – like HIV, hepatitis B and herpes – as well as autoimmune disorders and even for gene therapy.</p>
<h2>How can a vaccine treat cancers or chronic infectious diseases?</h2>
<p>T cell responses are very important for identifying cells infected with chronic diseases and aberrant cancer cells. They also play a big role in eliminating these cells from the body.</p>
<p>When a cell becomes cancerous, it <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/neoantigen">starts producing neoantigens</a>. In normal cases, the immune system detects these neoantigens, recognizes that something’s wrong with the cell and eliminates it. The reason some people get tumors is that their immune system isn’t quite capable of eliminating the tumor cells, so the cells propagate.</p>
<p>With an mRNA or DNA vaccine, the goal is to make your body better able to recognize the very specific neoantigens the cancer cell has produced. If your immune system can recognize and see those better, it will <a href="https://doi.org/10.1038/d41586-019-03072-8">attack the cancer cells and eliminate them from the body</a>. </p>
<p>This same strategy can be applied to the <a href="https://www.genengnews.com/insights/immunotherapy-targets-emerging-infectious-diseases/">elimination of chronic infections</a> like HIV, hepatitis B and herpes. These viruses infect the human body and stay in the body forever unless the immune system eliminates them. Similar to the way nucleic acid vaccines can train the immune system to eliminate cancer cells, they can be used to train our immune cells to recognize and eliminate chronically infected cells. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A syringe inserted into a vaccine vial." src="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">There are dozens of ongoing trials testing the efficacy of mRNA or DNA vaccines to treat cancers or chronic diseases.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/syringe-and-coronavirus-vaccine-royalty-free-image/1287271384?adppopup=true">Stefan Cristian Cioata/Moment via Getty Images</a></span>
</figcaption>
</figure>
<h2>What is the status of these vaccines?</h2>
<p>Some of the very first clinical trials of nucleic acid vaccines happened in the 1990s and <a href="https://doi.org/10.1073/pnas.90.23.11307">were for cancer</a>, particularly for <a href="https://doi.org/10.1038/nrg2432">melanoma</a>.</p>
<p>Today, there are a <a href="https://www.cancernetwork.com/view/messenger-rna-vaccines-beckoning-of-a-new-era-in-cancer-immunotherapy">number of ongoing mRNA clinical trials</a> for the treatment of melanoma, prostate cancer, ovarian cancer, breast cancer, leukemia, glioblastoma and others, and there have been some promising outcomes. Moderna recently announced promising results with its phase 1 trial using mRNA to <a href="https://www.businesswire.com/news/home/20211112005897/en/Moderna-Announces-Presentation-of-Interim-Data-from-Phase-1-Study-of-mRNA-Triplet-Program-at-2021-SITC-Annual-Meeting">treat solid tumors and lymphoma</a></p>
<p>There are also a lot of ongoing trials looking at cancer DNA vaccines, because DNA vaccines are <a href="https://doi.org/10.1186/s13046-019-1154-7">particularly effective in inducing T cell responses</a>. A company called Inovio recently demonstrated a significant impact on cervical cancer caused by human papilloma virus in women <a href="https://ir.inovio.com/news-releases/news-releases-details/2021/INOVIO-Highlights-Key-Updates-on-Phase-3-Program-for-VGX-3100-its-DNA-based-Immunotherapy-for-the-Treatment-of-Cervical-HSIL-Caused-by-HPV-16-andor-HPV-18/default.aspx">using a DNA vaccine</a>.</p>
<h2>Can nucleic acid vaccines treat autoimmune disorders?</h2>
<p>Autoimmune disorders occur when a person’s immune cells are actually attacking a part of the person’s own body. An example of this is multiple sclerosis. If you have multiple sclerosis, your <a href="https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269">own immune cells are attacking myelin</a>, a protein that coats the nerve cells in your muscles.</p>
<p>The way to eliminate an autoimmune disorder is to modulate your immune cells to prevent them from attacking your own proteins. In contrast to vaccines, whose goal is to stimulate the immune system to better recognize something, treatment for autoimmune diseases seeks to dampen the immune system so that it stops attacking something it shouldn’t. Recently, researchers created an mRNA vaccine encoding a myelin protein with slightly tweaked genetic instructions to prevent it from stimulating immune responses. Instead of activating normal T cells that increase immune responses, the vaccine caused the body to <a href="https://doi.org/10.1126/science.aay3638">produce T regulatory cells</a> that specifically suppressed only the T cells that were attacking myelin.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A diagram showing DNA turning into mRNA which turns into proteins." src="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=618&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=618&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=618&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=776&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=776&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=776&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Many diseases result when people have mutations or are missing certain genes, and nucleic acid vaccines could act as temporary replacements for the missing genes.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/mrna-and-protein-synthesis-difference-royalty-free-illustration/1323350905?adppopup=true">ttsz/iStock via Getty Images</a></span>
</figcaption>
</figure>
<h2>Any other applications of the new vaccine technology?</h2>
<p>The last application is actually one of the very first things that researchers thought about using DNA and mRNA vaccines for: gene therapy. Some people are born missing certain genes. The goal with gene therapy is to supply cells with the missing instructions they need to produce an important protein. </p>
<p>[<em>Over 140,000 readers rely on The Conversation’s newsletters to understand the world.</em> <a href="https://memberservices.theconversation.com/newsletters/?source=inline-140ksignup">Sign up today</a>.]</p>
<p>A great example of this is cystic fibrosis, a genetic disease caused by mutations in a single gene. Using DNA or an mRNA vaccine, researchers are investigating the feasibility of essentially replacing the missing gene and allowing someone’s body to <a href="https://www.cff.org/gene-therapy-cystic-fibrosis#rna-therapy">transiently produce the missing protein</a>. Once the protein is present, the symptoms could disappear, at least temporarily. The mRNA would not persist very long in the human body, nor would it integrate into people’s genomes or change the genome in any way. So additional doses would be needed as the effect wore off.</p>
<p>Research has shown that this concept is feasible, but it still needs some work.</p><img src="https://counter.theconversation.com/content/170772/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Deborah Fuller is co-founder of Orlance, Inc, a biotechnology company developing a needle free technology to deliver RNA and DNA vaccines. She also serves as a scientific advisor for HDT Bio, a biotechnology company developing RNA vaccines for COVID19 and other infectious diseases; scientific advisor for Abacus, Inc., a biotechnology company developing cancer vaccines and scientific advisor for SQZ Biotech, a biotechnology company developing cell-based therapies for cancer and infectious diseases. She is also serving as a vaccine expert for Wilmerhale on legal matters. She receives funding supporting basic and translational research in RNA and DNA vaccines from the National Institutes of Health.</span></em></p>DNA and mRNA vaccines produce a different kind of immune response than traditional vaccines, allowing researchers to tackle some previously unsolvable problems in medicine.Deborah Fuller, Professor of Microbiology, School of Medicine, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1675042021-09-10T11:52:49Z2021-09-10T11:52:49ZCholesterol jab: why gene silencing drugs may work better than current treatments<figure><img src="https://images.theconversation.com/files/420471/original/file-20210910-15-1kperel.jpg?ixlib=rb-1.1.0&rect=19%2C9%2C6470%2C4310&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The jab would be given twice a year.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/covid19-vaccine-vial-syring-coronavirus-sarscov2-1905018964">Girts Ragelis/ Shutterstock</a></span></figcaption></figure><p>The NHS has very recently approved a <a href="https://www.england.nhs.uk/2021/09/nhs-cholesterol-busting-jab-to-save-thousands-of-lives/">new cholesterol-lowering jab</a> which will be offered to 300,000 people over the next three years. </p>
<p><a href="https://www.bmj.com/content/368/bmj.m139">The drug</a> – inclisiran – will be administered twice a year as an injection. It will mainly be prescribed to patients who suffer with a genetic condition that leads to high cholesterol, those who have already suffered a heart attack or stroke, or those who haven’t responded well to other cholesterol-lowering drugs, such as statins.</p>
<p>There has been plenty of excitement surrounding the approval of the drug, both because of what it may be able to achieve, and because the drug uses a technique known as “gene silencing”. This is an emerging therapeutic technique that works by targeting the underlying causes of a disease, rather than the symptoms it causes. It does this by targeting a particular gene, and preventing it from making the protein that it produces.</p>
<p>Until now, most treatments using gene silencing technology have been used to treat rare genetic diseases. This means the cholesterol jab will be one of the first gene silencing drugs used to treat people on a wider scale. Researchers are also currently investigating whether gene silencing could be used to treat a wide variety of health conditions, including <a href="https://www.alzheimers.org.uk/blog/genetic-research-dementia-daniel-bradbury">Alzheimer’s disease</a> and <a href="https://www.frontiersin.org/articles/10.3389/fphar.2021.644718/full#:%7E:text=RNA%20interference%20(RNAi)%2C%20also,of%20treatments%2C%20particularly%20genetic%20therapies.">cancer</a>.</p>
<h2>Gene silencing</h2>
<p>Gene silencing drugs work by targeting a specific type of RNA (ribonucleic acid) in the body, called “messenger” RNA. RNAs are found in every cell of the body, and play an important role in the flow of genetic information. But messenger RNA (mRNA) is one of the most important types of RNA our body has, as it copies and carries genetic instructions from our DNA and makes specific proteins depending on the instructions.</p>
<p>In the case of the cholesterol jab, gene silencing works by targeting a protein called PCSK9 and degrading it. This protein is involved in regulating cholesterol in our bodies, but occurs in excess in people with high levels of LDL cholesterol (the “bad” cholesterol). Preventing this protein from being produced in the first place will reduce cholesterol levels.</p>
<p>In order to target this specific mRNA, researchers need to create a synthetic version of another type of RNA – called small interfering RNA (siRNA) – in the lab. This is a highly specific stretch of RNA which can be used to target specific mRNAs. In this case, the siRNA is designed to specifically target the mRNA which carries instructions for the PCSK9 protein. It binds to its target mRNA and destroys the instructions, which significantly reduces the amount of these proteins that are produced.</p>
<figure class="align-center ">
<img alt="Female doctor gives elderly patient an injection into his arm." src="https://images.theconversation.com/files/420472/original/file-20210910-14-gsthvo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/420472/original/file-20210910-14-gsthvo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/420472/original/file-20210910-14-gsthvo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/420472/original/file-20210910-14-gsthvo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/420472/original/file-20210910-14-gsthvo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/420472/original/file-20210910-14-gsthvo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/420472/original/file-20210910-14-gsthvo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The jab specifically targets the liver cells.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/seasonal-flu-shot-brazilian-nurse-medical-1633008724">Prostock-studio/ Shutterstock</a></span>
</figcaption>
</figure>
<p>Gene therapies are usually delivered using a viral vector – a virus-like vehicle that delivers genes to our cells in the same way a virus might infect them. So far, viral vector therapies have been used to treat rare <a href="https://rupress.org/jem/article/217/2/e20190607/132743/Gene-therapy-for-severe-combined">genetic blood disorders</a>, <a href="https://www.sciencedaily.com/releases/2019/09/190909170745.htm">genetic blindness</a> and <a href="https://www.ema.europa.eu/en/news/new-gene-therapy-treat-spinal-muscular-atrophy-corrected">spinal muscular atrophy</a>. </p>
<p>Although viral vectors are very effective with one treatment, it may be impossible to deliver a second dose if needed due to adverse immune reactions. These drugs are also <a href="https://www.npr.org/sections/health-shots/2019/05/24/725404168/at-2-125-million-new-gene-therapy-is-the-most-expensive-drug-ever?t=1631004513813">extremely costly</a>.</p>
<p>Because of this, many of the gene silencing drugs currently being investigated are delivered using a different technique. Known as non-viral vector gene therapies, these deliver the drug using a nanoparticle which protects it from degradation in the blood so it can be delivered specifically to the target – such as the liver, which is the target of the cholesterol jab.</p>
<p>Gene silencing therapies delivered by non-viral vectors seem to hold more promise as they can be administered several times with <a href="https://www.mdpi.com/1422-0067/22/14/7545">limited side effects</a>. Currently, non-viral vector therapies are used to treat a rare genetic condition called <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041433/">hereditary transthyretin-mediated amyloidosis</a>, as well as in mRNA vaccines, such as <a href="https://www.nature.com/articles/s41578-021-00281-4">BionTech/Pfizer and Moderna</a>. </p>
<p>Interestingly, though, the cholesterol jab is not buried inside a nanoparticle or delivered with a viral vector. Instead, the siRNA has been heavily modified in the lab to withstand degradation in the blood. It also has a ligand (a sugar molecule that works a bit like a hook) attached to it that allows it to specifically target liver cells.</p>
<h2>Future treatments</h2>
<p>Several more gene silencing drugs are currently being investigated to treat a <a href="https://www.nature.com/articles/s41392-020-0207-x">variety of other disorders</a>, including in the kidney (such as preventing adverse reactions after a transplant), the skin (scarring), cancer (including melanoma, prostate, pancreatic, brain and other tumours) and <a href="https://pubmed.ncbi.nlm.nih.gov/33548256/">eye disorders</a> (such as age-related macular degeneration and glaucoma). Researchers are also investigating whether gene silencing therapies could be useful in treating <a href="https://www.nature.com/articles/d41586-019-03069-3">neurological and brain disorders</a>, such as Huntington’s disease and Alzheimer’s disease. </p>
<p>Each of these gene silencing treatments would use similar techniques as other drugs that currently exist – by targeting a specific gene or protein and shutting it off. But in the case of cancer, because it’s very complex, multiple different proteins may need to be targeted. </p>
<p>These gene silencing technologies will need to be shown to be effective in further clinical trials before they can be rolled out for use on a wider scale. Another important challenge will be ensuring that the costs of these drugs remain low so many people can access them. But overall, these developments are very promising: gene silencing drugs are more specialised as they can target specific proteins in our cells. This may be why they can be more successful in treating diseases than current treatments.</p><img src="https://counter.theconversation.com/content/167504/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Aristides Tagalakis does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Gene silencing drugs target the underlying causes of a disease, rather than the symptoms it causes.Aristides Tagalakis, Reader in Gene Delivery and Nanomedicine, Edge Hill UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1649902021-08-31T12:28:57Z2021-08-31T12:28:57ZNew gene therapies may soon treat dozens of rare diseases, but million-dollar price tags will put them out of reach for many<figure><img src="https://images.theconversation.com/files/418515/original/file-20210830-22-1fltn8m.jpg?ixlib=rb-1.1.0&rect=248%2C144%2C8488%2C4217&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Gene therapy uses our genomic makeup to treat or prevent disease. </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/biotechnology-molecular-engineering-dna-genetic-royalty-free-image/1310024666">ktsimape/iStock via Getty Images</a></span></figcaption></figure><p><a href="https://theconversation.com/the-most-expensive-drug-in-the-world-how-it-works-and-the-devastating-disease-it-treats-164535">Zolgensma</a> – which treats <a href="https://www.mda.org/disease/spinal-muscular-atrophy">spinal muscular atrophy</a>, a rare genetic disease that damages nerve cells, leading to muscle decay – is currently the most expensive drug in the world. A one-time treatment of the life-saving drug for a young child <a href="https://www.npr.org/sections/health-shots/2019/05/24/725404168/at-2-125-million-new-gene-therapy-is-the-most-expensive-drug-ever">costs US$2.1 million</a>.</p>
<p>While Zolgensma’s exorbitant price is an outlier today, by the end of the decade there’ll be dozens of cell and gene therapies, costing hundreds of thousands to millions of dollars for a single dose. The Food and Drug Administration <a href="https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics">predicts that by 2025 it will be approving 10 to 20 cell and gene therapies</a> every year.</p>
<p>I’m a <a href="https://www.kevindoxzen.com/">biotechnology and policy expert</a> focused on improving access to cell and gene therapies. While these forthcoming treatments have the potential to save many lives and ease much suffering, health care systems around the world aren’t equipped to handle them. Creative new payment systems will be necessary to ensure everyone has equal access to these therapies. </p>
<h2>The rise of gene therapies</h2>
<p>Currently, only <a href="https://globalgenes.org/rare-facts/">5% of the roughly 7,000 rare diseases</a> have an FDA-approved drug, leaving thousands of conditions without a cure.</p>
<p>But over the past few years, genetic engineering technology has made <a href="https://www.genengnews.com/insights/the-outlook-for-2020-and-beyond/">impressive strides</a> toward the ultimate goal of curing disease by <a href="https://www.npr.org/sections/health-shots/2019/10/21/771266879/scientists-create-new-more-powerful-technique-to-edit-genes">changing a cell’s genetic instructions</a>.</p>
<p>The resulting <a href="https://theconversation.com/boyer-lectures-gene-therapy-is-still-in-its-infancy-but-the-future-looks-promising-104558">gene therapies</a> will be able to treat many diseases at the DNA level in a single dose. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786935/#:%7E:text=There%20are%205%2C000%E2%80%938%2C000%20monogenic,mutations%20on%20a%20single%20gene.">Thousands of diseases</a> are the result of DNA errors, which prevent cells from functioning normally. By directly correcting disease-causing mutations or altering a cell’s DNA to give the cell new tools to fight disease, <a href="https://theconversation.com/explainer-what-is-gene-therapy-19883">gene therapy</a> offers a powerful new approach to medicine.</p>
<p>There are <a href="https://asgct.org/global/documents/asgct-pharma-intelligence-quarterly-report-july-20.aspx?_zs=sisac&_zl=Uu4h2">1,745 gene therapies</a> in development around the world. A large fraction of this research focuses on rare genetic diseases, which affect <a href="https://globalgenes.org/rare-facts/">400 million people worldwide</a>. </p>
<p>We may soon see cures for rare diseases like <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2031054">sickle cell disease</a>, <a href="https://www.pnas.org/content/118/22/e2004840117">muscular dystrophy</a> and <a href="https://www.sciencemag.org/news/2021/01/incredible-gene-editing-result-mice-inspires-plans-treat-premature-aging-syndrome">progeria</a>, a rare and progressive genetic disorder that causes children to age rapidly. </p>
<p>Further into the future, gene therapies may help treat more common conditions, like <a href="https://www.nature.com/articles/d41586-018-02482-4">heart disease</a> and <a href="https://www.wsj.com/articles/crisprs-next-frontier-treating-common-conditions-11620226832">chronic pain</a>. </p>
<h2>Sky-high price tags</h2>
<p>The problem is these therapies will carry enormous price tags. </p>
<p>Gene therapies are the result of years of research and development totaling hundreds of millions to <a href="https://fortune.com/2020/02/07/zolgensma-high-drug-prices/">billions of dollars</a>. Sophisticated manufacturing facilities, highly trained personnel and complex biological materials set gene therapies apart from other drugs.</p>
<p>Pharmaceutical companies say recouping costs, especially for drugs with <a href="https://www.technologyreview.com/2017/10/24/148183/tracking-the-cost-of-gene-therapy/">small numbers of potential patients</a>, means higher prices.</p>
<p>The toll of high prices on health care systems will not be trivial. Consider a gene therapy cure for sickle cell disease, which is expected to be available in the next few years. The estimated price of this treatment is $1.85 million per patient. As a result, economists predict that it could cost a single state Medicare program <a href="https://www.doi.org/10.1001/jamapediatrics.2020.7140">almost $30 million per year</a>, even assuming only 7% of the eligible population received the treatment. </p>
<p>And that’s just one drug. Introducing dozens of similar therapies into the market would <a href="https://www.valueinhealthjournal.com/article/S1098-3015(19)30188-3/fulltext">strain health care systems</a> and create <a href="https://www.insurancejournal.com/news/national/2019/09/13/539591.htm">difficult financial decisions for private insurers</a>.</p>
<p>[<em>Over 110,000 readers rely on The Conversation’s newsletter to understand the world.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=100Ksignup">Sign up today</a>.]</p>
<h2>Lowering costs, finding new ways to pay</h2>
<p>One solution for improving patient access to gene therapies would be to simply demand drugmakers charge less money, a <a href="https://www.statnews.com/2021/04/22/bluebirds-withdrawal-of-therapy-from-germany-could-chill-talks-over-gene-therapy-prices-across-europe/">tactic recently taken in Germany</a>. </p>
<p>But this comes with a lot of challenges and may mean that companies <a href="https://www.fiercepharma.com/pharma/situation-untenable-bluebird-will-wind-down-its-operations-broken-europe">simply refuse to offer the treatment</a> in certain places.</p>
<p>I think a more balanced and sustainable approach is two-fold. In the short term, it’ll be important to develop new payment methods that entice insurance companies to cover high-cost therapies and distribute risks across patients, insurance companies and drugmakers. In the long run, improved gene therapy technology will inevitably help lower costs.</p>
<p>For innovative payment models, one tested approach is tying coverage to patient health outcomes. Since these therapies are still experimental and relatively new, there isn’t much data to help insurers make the risky decision of whether to cover them. If an insurance company is paying $1 million for a therapy, it had better work. </p>
<p>In <a href="https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/unlocking-market-access-for-gene-therapies-in-the-united-states">outcomes-based models</a>, insurers will either pay for some of the therapy upfront and the rest only if the patient improves, or cover the entire cost upfront and receive a reimbursement if the patient doesn’t get better. These models help insurers share financial risk with the drug developers.</p>
<p>Another model is known as the “<a href="https://www.doi.org/10.1377/hblog20190924.559225">Netflix model</a>” and would act as a subscription-based service. Under this model, a state Medicaid program would pay a pharmaceutical company a flat fee for access to unlimited treatments. This would allow a state to <a href="https://www.cnbc.com/2019/05/20/commentary-new-drug-cures-risk-widening-income-gap-for-the-poor.html">provide the treatment to residents who qualify</a>, helping governments balance their budget books while giving drugmakers money upfront. </p>
<p>This model has worked well for <a href="https://www.biopharmadive.com/news/cms-approves-louisianas-netflix-model-with-gilead-for-hepatitis-c-drugs/557708/">improving access to hepatitis C drugs in Louisiana</a>.</p>
<p>On the cost front, the key to improving access will be investing in new technologies that simplify medical procedures. For example, the costly sickle cell gene therapies currently in clinical trials require a series of expensive steps, including a stem cell transplant. </p>
<p>The <a href="https://www.gatesfoundation.org/ideas/articles/gene-therapy-mike-mccune">Bill & Melinda Gates Foundation</a>, the <a href="https://www.nih.gov/news-events/news-releases/nih-launches-new-collaboration-develop-gene-based-cures-sickle-cell-disease-hiv-global-scale">National Institute of Health</a> and <a href="https://www.novartis.com/news/media-releases/novartis-and-bill-melinda-gates-foundation-collaborate-discover-and-develop-accessible-vivo-gene-therapy-sickle-cell-disease">Novartis</a> are partnering to develop an alternative approach that would involve a simple injection of gene therapy molecules. The goal of their collaboration is to help bring an affordable sickle cell treatment to <a href="https://www.statnews.com/2019/10/23/nih-gates-foundation-genetic-cures-hiv-sickle-cell/">patients in Africa</a> and other low-resource settings. </p>
<p>Improving access to gene therapies requires collaboration and compromise across governments, nonprofits, pharmaceutical companies and insurers. Taking proactive steps now to develop innovative payment models and invest in new technologies will help ensure that health care systems are ready to deliver on the promise of gene therapies.</p>
<p><em>The Bill & Melinda Gates Foundation has provided funding for The Conversation US and provides funding for The Conversation internationally.</em></p><img src="https://counter.theconversation.com/content/164990/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kevin Doxzen is affiliated with Arizona State University and the World Economic Forum</span></em></p>New payment models may mean more of the people who need these treatments can get them.Kevin Doxzen, Hoffmann Postdoctoral Fellow, Arizona State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1637102021-08-09T19:17:46Z2021-08-09T19:17:46ZNew technology can create treatment against drug-resistant bacteria in under a week and adapt to antibiotic resistance<figure><img src="https://images.theconversation.com/files/413817/original/file-20210729-27-1det80r.jpg?ixlib=rb-1.1.0&rect=10%2C10%2C3468%2C3056&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Effective delivery of PNA therapies may offer a way to treat multidrug-resistant infections and other diseases.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/petri-dish-royalty-free-illustration/1184279986">sorbetto/DigitalVision Vectors via Getty Images</a></span></figcaption></figure><p><em>The <a href="https://theconversation.com/us/topics/research-brief-83231">Research Brief</a> is a short take about interesting academic work.</em></p>
<h2>The big idea</h2>
<p>A <a href="https://doi.org/10.1038/s42003-021-01856-1">new technique my colleagues and I developed</a> that can kill deadly, <a href="https://doi.org/10.1038/s42003-021-01856-1">multidrug-resistant bacteria</a> in real time could be used to generate targeted therapies that replace traditional, increasingly ineffective antibiotics.</p>
<p>Bacteria follow the <a href="https://www.yourgenome.org/facts/what-is-the-central-dogma">same basic genetic process</a> that all organisms do: DNA, which contains instructions on how an organism will look and function, is copied into an intermediate form called RNA that can be translated into proteins and other molecules the organism can use. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/410898/original/file-20210712-19-q986xg.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram of PNA interrupting the basic biological process of DNA being converted to protein." src="https://images.theconversation.com/files/410898/original/file-20210712-19-q986xg.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/410898/original/file-20210712-19-q986xg.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=411&fit=crop&dpr=1 600w, https://images.theconversation.com/files/410898/original/file-20210712-19-q986xg.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=411&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/410898/original/file-20210712-19-q986xg.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=411&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/410898/original/file-20210712-19-q986xg.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=517&fit=crop&dpr=1 754w, https://images.theconversation.com/files/410898/original/file-20210712-19-q986xg.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=517&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/410898/original/file-20210712-19-q986xg.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=517&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">PNAs can be introduced to interrupt the process in which DNA is converted into protein or other useful biological molecules necessary for life.</span>
<span class="attribution"><span class="source">Kristen Eller</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>The technique we developed at the <a href="https://www.colorado.edu/lab/chatterjeelab/">Chatterjee Lab</a> at the University of Colorado Boulder uses a synthetic version of RNA called <a href="https://www.atdbio.com/content/12/Nucleic-acid-analogues">PNA, or peptide nucleic acid</a>, to disrupt this basic process in bacteria. Our PNA molecule clings to the bacterial RNA, blocking it from carrying out its job. Because this molecule is a perfect match to bacterial RNA, it binds very tightly to the RNA and resists degradation. This means that it can not only escape the bacteria’s error detection processes but also prevent that RNA from being translated into proteins and other useful biological molecules. This impediment can be lethal to the bacteria.</p>
<p>Our study, which we recently published in Communications Biology, demonstrates the therapeutic potential of a technique that can design, synthesize and test PNA treatments in under a week. </p>
<p>Most antibiotics aren’t specific enough to target only infectious bacteria <a href="https://doi.org/10.3389/fmicb.2015.01543">without also destroying the body’s good bacteria</a>. Our technology, however, uses noninfectious versions of multidrug-resistant bacteria to create highly specific molecules. By targeting just the pathogen of interest, these PNA therapeutics may avoid the harm that current antibiotics pose to the body’s good bacteria.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/410896/original/file-20210712-49042-jisweu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram depicting a new methodology of designing, synthesizing, testing and delivering therapies against multidrug-resistant bacteria." src="https://images.theconversation.com/files/410896/original/file-20210712-49042-jisweu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/410896/original/file-20210712-49042-jisweu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/410896/original/file-20210712-49042-jisweu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/410896/original/file-20210712-49042-jisweu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/410896/original/file-20210712-49042-jisweu.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=504&fit=crop&dpr=1 754w, https://images.theconversation.com/files/410896/original/file-20210712-49042-jisweu.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=504&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/410896/original/file-20210712-49042-jisweu.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=504&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The Facile Accelerated Specific Therapeutic (FAST) platform can produce therapies against multidrug-resistant bacteria in under a week.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1038/s42003-021-01856-1">Kristen Eller</a>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Why it matters</h2>
<p>Bacteria’s adaptation to survive current antibiotics, or <a href="https://www.cdc.gov/drugresistance/about.html">antibiotic resistance</a>, is on the rise. </p>
<p>Medicine’s current arsenal of treatments mostly consist of naturally occurring antibiotics that were isolated <a href="https://sitn.hms.harvard.edu/flash/2018/less-rebooting-antibiotic-pipeline/">more than 30 years ago</a>. Discovery of new antibiotics in nature has stagnated while bacteria continue to evolve and evade current treatments. And even if scientists were to find a new natural antibiotic, research shows that bacteria will begin to develop resistance within <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/">as little as 10 years</a>, leaving us in the same predicament as before. </p>
<p>New types of therapies need to be considered for a <a href="https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf">post-antibiotic era</a>, a time when our arsenal of antibiotics is no longer effective. By using a system that can target specific bacteria and be continuously modified based on emerging resistance patterns, doctors would no longer have to rely on chance discoveries. Treatments can adapt with bacteria.</p>
<h2>What still isn’t known</h2>
<p>Although we explore multiple characteristics that determine which RNA sequences are the best targets, more research is necessary to identify the most effective PNA therapeutics against multidrug-resistant bacteria. As our study only tested our new strategy on cell cultures in the lab, we’ll also need to see how it works in living animals to maximize the effectiveness of this kind of treatment.</p>
<h2>What’s next</h2>
<p>Our team is currently testing the technology in different animal models against different types of infections. We are also exploring other PNA delivery options, including adapting our bacterial delivery system to probiotic strains so it can integrate with the existing healthy bacteria population in the body.</p>
<p>With further development, our goal is to adapt the platform to target diseases that also use the same basic genetic processes as bacteria, such as viral infections or cancer.</p>
<p>[<em>Get the best of The Conversation, every weekend.</em> <a href="https://theconversation.com/us/newsletters/weekly-highlights-61?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=weeklybest">Sign up for our weekly newsletter</a>.]</p><img src="https://counter.theconversation.com/content/163710/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kristen Eller does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Antibiotic resistance is one of the biggest public health threats in the world. New research, however, may have found a way to keep up with rapidly evolving bacteria.Kristen Eller, PhD Candidate in Chemical Engineering, University of Colorado BoulderLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1645352021-07-19T16:29:09Z2021-07-19T16:29:09ZThe ‘most expensive drug in the world’, how it works and the devastating disease it treats<figure><img src="https://images.theconversation.com/files/411699/original/file-20210716-13925-10txw.png?ixlib=rb-1.1.0&rect=2%2C0%2C732%2C478&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Spinal muscula atrophy causes muscle wasting and loss of control, usually starting in infancy.</span> <span class="attribution"><a class="source" href="https://orthopaedia.com/page/Spinal-Muscular-Atrophy">Orthopedia/Codman Group</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p>Babies born with the rare, inherited motor neuron disease spinal muscular atrophy are, without treatment, unlikely to reach their second birthday. When, as a researcher in the 1990s, I became aware of the disease there were no treatments even on the horizon. Now there are two recently licensed drugs to treat this devastating affliction.</p>
<p>There is a catch, of course. One of these drugs, Zolgensma, which has <a href="https://www.theguardian.com/society/2021/jul/11/baby-gets-go-ahead-for-worlds-most-expensive-drug-from-nhs">just been made available</a> to treat babies in the UK, has been called “the most expensive drug in the world”. At £1.79 million for a dose, that’s probably true. </p>
<p>Spinal muscular atrophy is caused by the loss of a gene called survival motor neurons 1 (SMN1), which carries the information needed to make a protein, also called SMN, that is needed by every cell in the body. While in other species losing the SMN1 gene would be fatal, humans have an extra gene (SMN2) that can partly compensate for its loss. But SMN2 can generate only a small amount of the necessary protein compared to SMN1. And while many cells and organs in the body seem able to function with this reduced supply, motor neurons responsible for sending messages from the brain to the muscles are exquisitely sensitive to low levels of SMN. </p>
<p>This causes the loss of muscular control that is the characteristic symptom of the disease – where, for example, babies with the most common spinal muscular atrophy, type 1, usually fail to reach the developmental milestones such as actively rolling, sitting or crawling that most of us, as parents, take for granted. Other, milder <a href="https://www.nhs.uk/conditions/spinal-muscular-atrophy-sma/types/">types of the disease</a> appear later in childhood (types 2 and 3) or in young adults (type 4), and result in progressive loss of muscle function. Some adults with the disease, such as <a href="https://twitter.com/KylaHollywood">Michaela Hollywood</a>, work to raise awareness of it.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1412145089636409345"}"></div></p>
<p>As biologists we don’t understand why motor neurons are so sensitive to the reduction of SMN protein, largely because the protein has many different jobs within the cell which we don’t yet understand. </p>
<h2>Two pioneering drugs</h2>
<p>Two treatments for spinal muscular atrophy increase the amount of SMN protein present in patients, with both designed to deliver the maximum effect in motor neurons. </p>
<p><a href="https://www.spinraza.com/en_us/home/why-spinraza/how-spinraza-works.html">Spinraza</a> (generic name nusinersen) was the first accessible treatment, <a href="https://www.reuters.com/article/uk-biogen-england-idUKKCN1SK2QH">available through the NHS since 2019</a>. Spinraza is an <a href="https://www.nature.com/articles/nrneurol.2017.148">anti-sense oligonucleotide</a>, essentially a very small piece of DNA that targets the way the SMN2 gene creates the protein the body needs. Usually a cell makes a copy of the information carried by the gene, called messenger RNA, and processes it into a template to create the protein. The SMN2 gene has a tiny fault that affects the processing of the RNA, which is why it produces much less protein. Spinraza corrects this fault, and so increases the gene’s capacity to create protein.</p>
<p>To get Spinraza into motor neurons, the drug needs to be injected directly into the spinal column by lumbar puncture. Unpleasant at the best of times, this can be particularly challenging in older children and adults living with the disease, as spinal curvature is common. It also needs to be administered regularly: up to six injections in the first year of treatment at a cost of £75,000 per injection, and three each year after that. </p>
<p>The most recent treatment is <a href="https://www.zolgensma.com/how-zolgensma-works">Zolgensma</a> (generic name onasemnogene abeparvovec), a pioneering gene therapy dubbed “the most expensive drug in the world” and only <a href="https://www.theguardian.com/society/2021/mar/08/nhs-use-worlds-most-expensive-drug-treat-spinal-muscular-atrophy-zolgensma">available through the NHS since March 2021</a>. Zolgensma uses a harmless virus with some of its DNA replaced by a copy of the human SMN1 gene. The virus has been developed for its ability to deliver the SMN1 gene to motor neurons when injected into the bloodstream. With the new, replacement copy of the SMN1 gene, the motor neurons can generate more of the protein they need. </p>
<p>As well as being substantially easier and less invasive to administer, clinical trials suggest that only one dose of Zolgensma is needed for it to be effective, in contrast to the repeated maintenance doses needed for Spinraza.</p>
<h2>The future</h2>
<p>But neither of these drugs can be regarded as a complete cure, particularly for patients who have already developed significant symptoms. The timing of treatment for patients is critical, as the human body cannot replace motor neurons once they are lost. Ideally, treatment would be carried out before symptoms had developed. This is especially important for Zolgensma, which is currently only approved for babies under six months. </p>
<p>But in the UK newborns are not routinely screened for the disease, meaning some babies who could benefit from treatment may be missed, or that treatment begun later will be less effective. This is why campaigners are <a href="https://petition.parliament.uk/petitions/588447">petitioning parliament</a> to introduce screening for spinal muscular atrophy for newborns.</p>
<p>What’s critical is that we understand the long-term future for people treated with current therapies. We know lowered levels of SMN protein are particularly damaging to motor neurons, but we don’t know why. Other organs and tissues are also vulnerable to the effects of SMN loss, and we may need new treatments in the future to address this, given that these current drugs restore the supply of the protein primarily to motor neurons. </p>
<p>There is also some evidence from early <a href="https://journals.biologists.com/jcs/article/116/10/2039/27228/Cajal-body-proteins-SMN-and-Coilin-show">cell culture experiments</a> and more recent <a href="https://www.nature.com/articles/s41593-021-00827-3">animal models</a> that too much SMN protein may also be damaging to some cell types, particularly in the longer term. If this “Goldilocks effect” – neither too much, nor too little – poses problems for patients in the future, we need to work on the solutions now.</p>
<p>The list prices for both treatments are undeniably eye-watering, but “<a href="https://www.england.nhs.uk/2021/03/nhs-england-strikes-deal-on-life-saving-gene-therapy-drug-that-can-help-babies-with-rare-genetic-disease-move-and-walk/">deals have been struck</a>” by the NHS, and competition between these and future drugs may drive prices down.</p>
<p>In any case it is an enormously exciting time for people living with spinal muscular atrophy, their families and scientists working on it, with available therapies showing results that were the stuff of dreams only a couple of decades ago. But there is a long way to go before we can declare that this is a disease we can cure.</p><img src="https://counter.theconversation.com/content/164535/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Judith Sleeman receives funding from Muscular Dystrophy UK, MND Scotland, MRC, BBSRC and the Wellcome Trust. She is affiliated with MND Scotland. </span></em></p>Spinal muscular dystrophy affects at least 1 in 10,000 people, but new drugs have given hope to those suffering from this rare disease.Judith Sleeman, Senior Lecturer in Cell Biology, University of St AndrewsLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1536412021-02-01T18:58:20Z2021-02-01T18:58:20ZNew CRISPR technology could revolutionise gene therapy, offering new hope to people with genetic diseases<figure><img src="https://images.theconversation.com/files/381591/original/file-20210201-13-qr3zh4.jpg?ixlib=rb-1.1.0&rect=47%2C4%2C3147%2C1571&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>The day a muddled mob stormed the US Capitol building, a team of American researchers published a paper <a href="https://www.nature.com/articles/s41586-020-03086-7">in Nature</a> that signified a landmark in gene therapy.</p>
<p>The head of the US National Institutes of Health, Francis Collins had joined forces with Harvard University professor David Liu and others to tackle progeria, a genetic disorder that causes children to age rapidly. </p>
<p>The achievement, successfully tested in mice, was made possible by Liu’s invention of a second-generation CRISPR gene-editing technology called “base editing”. With this, researchers may eventually be able to correct lifelong genetic diseases, including <a href="https://www.webmd.com/children/progeria#1">progeria</a>, in humans.</p>
<h2>A rare but devastating disease</h2>
<p>Francis Collins, former leader of the Human Genome Project, had worked on progeria for many years before the breakthrough. </p>
<p>Children carrying the mutation for progeria have normal intelligence but show early signs of general ageing, including hair loss and hearing loss. By their teenage years they appear very old. Few live past the age of 13. </p>
<p>In 2003, Collins’s lab <a href="https://directorsblog.nih.gov/tag/progeria/">discovered</a> progeria is caused by a mutation (which you can think of as a “misspelling”) in a gene that encodes a protein called Lamin A. Lamin A has a structural role in the cell’s nucleus. </p>
<p>Many of us carry mutations in various genes. But as we typically have two copies of genes (one from our mother and one from our father), we tend to have at least one good copy and that’s usually enough.</p>
<p>But the progeria mutation in Lamin A is different. While there may be a good copy present, the mutant copy generates a poisonous product that messes things up, like a spanner in the works. This type of mutation is called a “dominant negative mutation”.</p>
<p>The solution, ideally, would be to specifically correct the mutant copy using <a href="https://theconversation.com/what-is-crispr-gene-editing-and-how-does-it-work-84591">CRISPR</a>. With this gene-editing tool, scientists can direct a pair of molecular “scissors” to any part of the genome (DNA). Unfortunately, first-generation CRISPR technologies — while good at cutting genes — do not have the level of surgical precision or efficiency needed to correct the Lamin A mutation. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-a-gene-12951">Explainer: what is a gene?</a>
</strong>
</em>
</p>
<hr>
<h2>Complications with mass cell editing</h2>
<p>CRISPR scissors are good at finding their target and cutting, but the reconstructive surgery that comes after is left to the cell — and isn’t guaranteed to happen in every cell. </p>
<p>In the lab, researchers can usually manage by just correcting a few cells before growing them in a petri dish for further research. </p>
<p>But in humans we need to accurately correct most, if not all, cells. It would be pointless to correct the progeria mutation in five cells in a patient’s finger, while leaving the rest of the body unrepaired.</p>
<p>This is where David Liu’s work on “base editors” is critical. Liu identified the limitations of CRISPR technology very early and began developing molecular machines that could do more than operate only as targeted molecular scissors. </p>
<p>He started with naturally occurring enzymes, which can change one type of chemical base of the genetic code into another; for example, enzymes that can convert an A (adenine) to a G (guanine), or a C (cytosine) to a T (thymine).</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram showing basic DNA structure and chemical bases." src="https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/381581/original/file-20210201-23-o5yyqz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The double helix shape of DNA is supported by an alternating sugar-phsophate backbone (the sides). Attached to each sugar on the backbone is one of four chemical bases: adenine (A), thymine (T), guanine (G) and cytosine (C). The order of these bases is what determines an organism’s genetic code.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>Liu then modified the enzymes to make them more precise and fused them to CRISPR to create fusion proteins called “base editors”. Since CRISPR technology is good at reading DNA and finding a target, it can effectively deliver the editors to the gene that needs to be changed.</p>
<p>It’s important to highlight Liu deliberately developed base editors so that they change letters, but no longer sever DNA like CRISPR scissors. This is crucial, as cutting DNA increases the risk of larger chromosomal deletions, which can potentially damage cells.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/the-resilience-project-finding-those-rare-people-with-genetic-disease-mutations-who-are-healthy-57800">The Resilience Project: finding those rare people with genetic disease mutations who are healthy</a>
</strong>
</em>
</p>
<hr>
<h2>The differences of mice and men</h2>
<p>Collins, Liu and their colleagues knew they would have to get base editors into all (or at least <em>most</em>) of the cells of a mouse with progeria to cure it. For this, they relied on using hollowed-out viruses as delivery vectors. </p>
<p>They used a vector based on the Adeno Associated Virus, or AAV. As students, we joked AAV stood for “almost a virus”, as it’s one of the smallest viruses and doesn’t cause any known disease. </p>
<p>Collins and Liu packaged the AAV virus particles with genes encoding the relevant base-editing enzyme and delivered them into the mice. The treated mice essentially avoided the disease and became indistinguishable from healthy mice.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/GO306dK8m8c?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">In this video, Collins and Lui discuss their work involving treating progeria in mice.</span></figcaption>
</figure>
<p>But, of course, this all happened in mice — and humans are bigger. We don’t know how difficult it will be to upscale this gene-editing machinery to work reliably in humans. But in any case, Collins and Liu have taken an inspiring first step by showing it’s possible in mice. </p>
<p>Base-editing CRISPR tools are a dream come true for experts committed to gene therapy and for families afflicted by conditions such as progeria. Work on this front is just beginning. But in these dark pandemic times, it provides much-needed new hope.</p><img src="https://counter.theconversation.com/content/153641/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Merlin Crossley works for UNSW as Deputy Vice-Chancellor Academic and Student Experience, and a Professor of Molecular Biology. He holds or has held Australian Research Council and National Health and Medical Research Council grants, and collaborates with biotechnology companies, such as CSL and various international labs doing CRISPR-gene editing. He is on the Board of The Conversation, and Chair of the Editorial Board, Chair of UNSW Press, Deputy Director of the Australian Science Media Centre, and is an Honorary Associate of the Australian Museum. </span></em></p>Using ‘base editing’, researchers have cured progeria in mice. This genetic syndrome causes premature ageing in humans – those with the disease usually don’t live past the age of 13.Merlin Crossley, Deputy Vice-Chancellor Academic and Professor of Molecular Biology, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1453672020-09-03T15:26:44Z2020-09-03T15:26:44ZCRISPR can help combat the troubling immune response against gene therapy<figure><img src="https://images.theconversation.com/files/356159/original/file-20200902-24-lmdp9z.jpg?ixlib=rb-1.1.0&rect=15%2C15%2C5176%2C5176&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Introducing healthy genes to replace defective ones is the essence of gene therapy.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/gene-therapy-royalty-free-image/574880295?adppopup=true">KTSFotos/Getty Images</a></span></figcaption></figure><p>One of the <a href="https://doi.org/10.1016/j.ymthe.2020.01.001">major challenges facing gene therapy</a> - a way to treat disease by replacing a patient’s defective genes with healthy ones - is that it is difficult to safely deliver therapeutic genes to patients without the immune system destroying the gene, and the vehicle carrying it, which can trigger life-threatening widespread inflammation.</p>
<p>Three decades ago researchers thought that gene therapy would be the ultimate treatment for genetically inherited diseases like <a href="https://ghr.nlm.nih.gov/condition/hemophilia">hemophilia</a>, <a href="https://www.nhlbi.nih.gov/health-topics/sickle-cell-disease">sickle cell anemia</a> and genetic diseases of metabolism. But the technology couldn’t dodge the immune response.</p>
<p>Since then, researchers have been looking for ways to perfect the technology and control immune responses to the gene or the vehicle. However, many of the strategies tested so far have <a href="https://www.sciencemag.org/news/2020/06/two-deaths-gene-therapy-trial-rare-muscle-disease">not been completely successful</a> <a href="https://www.sciencehistory.org/distillations/the-death-of-jesse-gelsinger-20-years-later">in overcoming this hurdle</a>. </p>
<p>Drugs that suppress the whole immune system, such as steroids, have been used to dampen the immune response when administering gene therapy. But it’s difficult to control when and where steroids work in the body, and they create unwanted side effects. My colleague <a href="http://www.ebrahimkhanilab.com">Mo Ebrahimkhani</a> and I wanted to tackle gene therapy with immune-suppressing tools that were easier to control.</p>
<p><a href="https://www.kianilab.com">I am a medical doctor and synthetic biologist</a> interested in gene therapy because six years ago my father was diagnosed with <a href="https://www.cancer.gov/types/pancreatic">pancreatic cancer</a>. Pancreatic cancer is one of the deadliest forms of cancer, and the current available therapeutics usually fail to save patients. As a result, novel treatments such as gene therapy might be the only hope.</p>
<p>Yet, many gene therapies fail because patients either already have pre-existing immunity to the vehicle used to introduce the gene or develop one in the course of therapy. This problem has plagued the field for decades, preventing the widespread application of the technology.</p>
<h2>Gene therapy: past and present</h2>
<p>Traditionally scientists use viruses - from which dangerous disease-causing genes have been removed - as vehicles to transport new genes to specific organs. These genes then produce a product that can compensate for the faulty genes that are inherited genetically. This is how gene therapy works. </p>
<p>Though there <a href="https://www.asgct.org/research/news/april-2020/world-hemophilia-day">have been examples</a> showing that <a href="https://www.labiotech.eu/medical/bluebird-bio-gene-therapy-thalassemia/">gene therapy was helpful</a> in some genetic diseases, they are still not perfect. Sometimes, a faulty gene is so big that you can’t simply fit the healthy replacement in the viruses commonly used in gene therapy.</p>
<p>Another problem is that when the immune system sees a virus, it assumes that it is a disease-causing pathogen and launches an attack to fight it off by producing antibodies and immune response – just as happens when people catch any other infectious viruses, like SARS-CoV-2 or the common cold. </p>
<p>Recently, though, with the rise of a <a href="https://www.sciencenewsforstudents.org/article/explainer-how-crispr-works">gene editing technology called CRISPR</a>, scientists can do gene therapy differently.</p>
<p>CRISPR can be used in many ways. In its primary role, it acts like a genetic surgeon with a sharp scalpel, enabling scientists to find a genetic defect and correct it within the native genome in desired cells of the organism. It can also repair more than one gene at a time. </p>
<p>Scientists can also use CRISPR to turn off a gene for a short period of time and then turn it back on, or vice versa, without permanently changing the letters of DNA that makes up or genome. This means that researchers like me can leverage CRISPR technology to revolutionize gene therapies in the coming decades.</p>
<p>But to use CRISPR for either of these functions, it still needs to be packaged into a virus to get it into the body. So some challenges, such as preventing the immune response to the gene therapy viruses, still need to be solved for CRISPR-based gene therapies. </p>
<p>Being trained as <a href="http://www.kianilab.com">a synthetic biologist</a>, I teamed up with Ebrahimkhani to use CRISPR to test whether we could shut down a gene that is responsible for immune response that destroys the gene therapy viruses. Then we investigated whether lowering the activity of the gene, and dulling the immune response, would allow the gene therapy viruses to be more effective.</p>
<p>[<em>Deep knowledge, daily.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=deepknowledge">Sign up for The Conversation’s newsletter</a>.]</p>
<h2>Preventing the immune response that destroys gene therapy viruses</h2>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/356160/original/file-20200902-14-5r5jt3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/356160/original/file-20200902-14-5r5jt3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/356160/original/file-20200902-14-5r5jt3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=688&fit=crop&dpr=1 600w, https://images.theconversation.com/files/356160/original/file-20200902-14-5r5jt3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=688&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/356160/original/file-20200902-14-5r5jt3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=688&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/356160/original/file-20200902-14-5r5jt3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=864&fit=crop&dpr=1 754w, https://images.theconversation.com/files/356160/original/file-20200902-14-5r5jt3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=864&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/356160/original/file-20200902-14-5r5jt3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=864&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">CRISPR can precisely remove even single units of DNA.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/gene-editing-conceptual-illustration-royalty-free-illustration/1015902954?adppopup=true">KEITH CHAMBERS/SCIENCE PHOTO LIBRARY/Getty Images</a></span>
</figcaption>
</figure>
<p><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=MYD88">A gene called Myd88</a> is a key gene in the immune system and controls the response to bacteria and viruses, including the common gene therapy viruses. We decided to temporarily turn off this gene in the whole body of lab animals. </p>
<p>We injected animals with a collection of the CRISPR molecules that targeted the Myd88 gene and looked to see whether this reduced the quantity of antibodies that were produced to specifically fight our gene therapy viruses. We were excited to see that the animals that received our treatment using CRISPR produced less antibody against the virus.</p>
<p>This prompted us to ask what happens if we give the animal a second dose of the gene therapy virus. Usually the immune response against a gene therapy virus prevents the therapy from being administered multiple times. That’s because after the first dose, the immune system has seen the virus, and on the second dose, antibodies swiftly attack and destroy the virus before it can deliver its cargo.</p>
<p>We saw that animals receiving more than one dose did not show an increase in antibodies against the virus. And, in some cases, the effect of gene therapy improved compared with the animals in which we had not paused the Myd88 gene. </p>
<p>We also did a number of other experiments that proved that tweaking the Myd88 gene can be useful in fighting off other sources of inflammation. That could be useful in diseases like sepsis and even COVID-19. </p>
<p>While we are now beginning to improve this strategy in terms of controlling the activity of the Myd88 gene. Our results, now published in <a href="https://www.nature.com/articles/s41556-020-0563-3">Nature Cell Biology</a>,
provide a path forward to program our immune system during gene therapies and other inflammatory responses using the CRISPR technology.</p><img src="https://counter.theconversation.com/content/145367/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Samira Kiani is a co-founder and founding CSO of Safegen Therapeutics. She receives funding from National Institute of Health for her research program.</span></em></p>The immune system is trained to destroy viruses, even when they carry therapeutic cargo as is the case in gene therapy. Now researchers have figured out how to dial down the immune response.Samira Kiani, Associate Professor of Pathology, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1332202020-06-25T12:24:34Z2020-06-25T12:24:34ZGene therapy and CRISPR strategies for curing blindness (Yes, you read that right)<figure><img src="https://images.theconversation.com/files/343286/original/file-20200622-54993-o5z60d.jpg?ixlib=rb-1.1.0&rect=15%2C7%2C5106%2C3394&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Researchers are now testing treatments for several kinds of visual impairment. </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/blind-10-year-old-boy-reading-a-braille-book-royalty-free-image/523091364?adppopup=true&uiloc=thumbnail_same_series_adp">BRIAN MITCHELL / Getty Images</a></span></figcaption></figure><p>In recent months, even as our attention has been focused on the coronavirus outbreak, there have been a slew of scientific breakthroughs in treating diseases that cause blindness. </p>
<p>Researchers at U.S.-based Editas Medicine and Ireland-based Allergan have administered <a href="https://clinicaltrials.gov/ct2/show/NCT03872479">CRISPR for the first time to a person with a genetic disease</a>. This landmark treatment uses the CRISPR approach to a specific mutation in a gene linked to childhood blindness. The mutation affects the functioning of the light-sensing compartment of the eye, called the retina, and leads to loss of the light-sensing cells.</p>
<p>According to the World Health Organization, <a href="https://www.who.int/news-room/detail/08-10-2019-who-launches-first-world-report-on-vision">at least 2.2 billion people</a> in the world have some form of visual impairment. In the United States, approximately <a href="https://lowvision.preventblindness.org/2013/07/06/numbers-of-people-with-macular-degeneration-and-other-retinal-diseases/">200,000 people suffer from inherited forms of retinal disease</a> for which there is no cure. But things have started to change for good. We can now see light at the end of the tunnel.</p>
<p>I am an ophthalmology and visual sciences researcher, and am particularly interested in these advances because <a href="https://www.umassmed.edu/khannalab/">my laboratory is focusing</a> on designing new and improved gene therapy approaches to treat inherited forms of blindness. </p>
<h2>The eye as a testing ground for CRISPR</h2>
<p>Gene therapy involves inserting the correct copy of a gene into cells that have a mistake in the genetic sequence of that gene, recovering the normal function of the protein in the cell. The eye is an ideal organ for testing new therapeutic approaches, including CRISPR. That is because the eye is the most exposed part of our brain and thus is easily accessible. </p>
<p>The second reason is that retinal tissue in the eye is shielded from the body’s defense mechanism, which would otherwise consider the injected material used in gene therapy as foreign and mount a defensive attack response. Such a response would destroy the benefits associated with the treatment. </p>
<p>In recent years, breakthrough gene therapy studies paved the way to the <a href="https://www.fda.gov/news-events/press-announcements/fda-approves-novel-gene-therapy-treat-patients-rare-form-inherited-vision-loss">first ever Food and Drug Administration-approved gene therapy drug, Luxturna TM</a>, for a devastating childhood blindness disease, <a href="https://ghr.nlm.nih.gov/condition/leber-congenital-amaurosis">Leber congenital amaurosis</a> Type 2. </p>
<p>This form of Leber congenital amaurosis is caused by mutations in a gene that codes for a protein called RPE65. The protein participates in chemical reactions that are needed to detect light. The mutations lessen or eliminate the function of RPE65, which leads to our inability to detect light – blindness. </p>
<p>The treatment method developed simultaneously by groups at University of Pennsylvania and at University College London and Moorefields Eye Hospital involved <a href="https://www.nature.com/news/2008/080428/full/news.2008.786.html">inserting a healthy copy of the mutated gene</a> directly into the space between the retina and the retinal pigmented epithelium, the tissue located behind the retina where the chemical reactions takes place. This gene helped the retinal pigmented epithelium cell produce the missing protein that is dysfunctional in patients. </p>
<p>Although the treated eyes showed vision improvement, as measured by the patient’s ability to navigate an obstacle course at differing light levels, <a href="https://www.aop.org.uk/ot/science-and-vision/research/2015/05/05/lca-gene-therapy-unable-to-stop-long-term-sight-loss">it is not a permanent fix</a>. This is due to the lack of technologies that can fix the mutated genetic code in the DNA of the cells of the patient. </p>
<h2>A new technology to erase the mutation</h2>
<p>Lately, scientists have been developing a powerful new tool that is shifting biology and genetic engineering into the next phase. This breakthrough <a href="http://doi.org/10.1126/science.1225829">gene</a> <a href="http://doi.org/10.1126/science.1231143">editing</a> technology, which is called CRISPR, enables researchers to directly edit the genetic code of cells in the eye and correct the mutation causing the disease. </p>
<p>Children suffering from the disease Leber congenital amaurosis Type 10 endure progressive vision loss beginning as early as one year old. This specific form of Leber congenital amaurosis is caused by a change to the DNA that affects the ability of the gene – called CEP290 – to make the complete protein. The loss of the CEP290 protein affects the survival and function of our light-sensing cells, called photoreceptors. </p>
<p>One treatment strategy is to deliver the full form of the CEP290 gene using a virus as the delivery vehicle. But the CEP290 gene is too big to be cargo for viruses. So another approach was needed. One strategy was to fix the mutation by using CRISPR.</p>
<p>The scientists at Editas Medicine first showed safety and proof of the concept of the CRISPR strategy in cells extracted from patient skin biopsy and in nonhuman primate animals. </p>
<p>These studies led to the formulation of the <a href="https://ir.editasmedicine.com/news-releases/news-release-details/allergan-and-editas-medicine-announce-dosing-first-patient">first ever in human CRISPR gene therapeutic clinical trial</a>. This Phase 1 and Phase 2 trial will eventually assess the safety and efficacy of the CRISPR therapy in 18 Leber congenital amaurosis Type 10 patients. The patients receive a dose of the therapy while under anesthesia when the retina surgeon uses a scope, needle and syringe to inject the CRISPR enzyme and nucleic acids into the back of the eye near the photoreceptors. </p>
<p>To make sure that the experiment is working and safe for the patients, the clinical trial has recruited people with late-stage disease and no hope of recovering their vision. The doctors are also injecting the CRISPR editing tools into only one eye. </p>
<h2>A new CEP290 gene therapy strategy</h2>
<p>An ongoing project in my laboratory focuses on designing a gene therapy approach for the same gene CEP290. Contrary to the CRISPR approach, which can target only a specific mutation at one time, my team is developing an approach that would work for all CEP290 mutations in Leber congenital amaurosis Type 10. </p>
<p>This approach involves using <a href="https://www.umassmed.edu/khannalab/ciliopathies-blog-and-news/channa-lab-in-the-news/2017/September/study-shows-potential-of-cep290-minigenes-as-therapeutics-for-childhood-blindness-disorder/">shorter yet functional forms of the CEP290 protein</a> that can be delivered to the photoreceptors using the viruses approved for clinical use.</p>
<p>Gene therapy that involves CRISPR promises a permanent fix and a significantly reduced recovery period. A downside of the CRISPR approach is the possibility of an off-target effect in which another region of the cell’s DNA is edited, which could cause undesirable side effects, such as cancer. However, new and improved strategies have made such likelihood very low. </p>
<p>Although the CRISPR study is for a specific mutation in CEP290, I believe the use of CRISPR technology in the body to be exciting and a giant leap. I know this treatment is in an early phase, but it shows clear promise. In my mind, as well as the minds of many other scientists, CRISPR-mediated therapeutic innovation absolutely holds immense promise. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/343289/original/file-20200622-54977-16bxxmw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/343289/original/file-20200622-54977-16bxxmw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/343289/original/file-20200622-54977-16bxxmw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/343289/original/file-20200622-54977-16bxxmw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/343289/original/file-20200622-54977-16bxxmw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/343289/original/file-20200622-54977-16bxxmw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/343289/original/file-20200622-54977-16bxxmw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/343289/original/file-20200622-54977-16bxxmw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">An infrared image of a man and a dog. German and Swiss researchers have shown that they can endow living mice with this type of vision.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/thermal-image-of-man-with-dog-royalty-free-image/758300683?adppopup=true">Joseph Giacomin</a></span>
</figcaption>
</figure>
<h2>More ways to tackle blindness</h2>
<p>In another study just reported in the journal Science, German and Swiss scientists have developed <a href="https://doi.org/10.1126/science.aaz5887">a revolutionary technology</a>, which enables mice and human retinas to detect infrared radiation. This ability could be useful for patients suffering from loss of photoreceptors and sight. </p>
<p>The researchers demonstrated this approach, inspired by the ability of snakes and bats to see heat, by endowing mice and postmortem human retinas with a protein that becomes active in response to heat. Infrared light is light emitted by warm objects that is beyond the visible spectrum. </p>
<p>The heat warms a specially engineered gold particle that the researchers introduced into the retina. This particle binds to the protein and helps it convert the heat signal into electrical signals that are then sent to the brain. </p>
<p>In the future, more research is needed to tweak the ability of the infrared sensitive proteins to different wave lengths of light that will also enhance the remaining vision. </p>
<p>This approach is still being tested in animals and in retinal tissue in the lab. But all approaches suggest that it might be possible to either restore, enhance or provide patients with forms of vision used by other species.</p>
<p>[<em>Get our best science, health and technology stories.</em> <a href="https://theconversation.com/us/newsletters/science-editors-picks-71/?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=science-best">Sign up for The Conversation’s science newsletter</a>.]</p><img src="https://counter.theconversation.com/content/133220/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Hemant Khanna receives funding from National Institutes of Health and Iveric Bio. </span></em></p>Strategies to cure various types of blindness are looking more plausible after a series of recent breakthroughs using gene editing and gene therapy.Hemant Khanna, Associate Professor of Ophthalmology, UMass Chan Medical SchoolLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1305682020-02-11T13:53:48Z2020-02-11T13:53:48ZWhy sequencing the human genome failed to produce big breakthroughs in disease<figure><img src="https://images.theconversation.com/files/314042/original/file-20200206-43089-1b0x437.jpg?ixlib=rb-1.1.0&rect=17%2C8%2C5973%2C3440&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Early proponents of genome sequencing made misleading predictions about its potential in medicine.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/innovative-science-medicine-concept-design-576826981">Natali_ Mis/Shutterstock.com</a></span></figcaption></figure><p>An emergency room physician, initially unable to diagnose a disoriented patient, finds on the patient a wallet-sized card providing access to his genome, or all his DNA. The physician quickly searches the genome, diagnoses the problem and sends the patient off for a gene-therapy cure. That’s what a Pulitzer prize-winning <a href="https://www.latimes.com/archives/la-xpm-1996-03-03-tm-42636-story.htm">journalist imagined</a> 2020 would look like when she reported on the Human Genome Project back in 1996.</p>
<h2>A new era in medicine?</h2>
<p>The Human Genome Project was an international scientific collaboration that successfully mapped, sequenced and made publicly available the genetic content of human chromosomes – or all human DNA. Taking place between 1990 and 2003, the project caused many to speculate about the future of medicine. In 1996, Walter Gilbert, a Nobel laureate, <a href="https://www.latimes.com/archives/la-xpm-1996-03-03-tm-42636-story.html">said</a>, “The results of the Human Genome Project will produce a tremendous shift in the way we can do medicine and attack problems of human disease.” In 2000, Francis Collins, then head of the HGP at the National Institutes of Health, <a href="https://web.ornl.gov/sci/techresources/Human_Genome/project/clinton3.shtml">predicted</a>, “Perhaps in another 15 or 20 years, you will see a complete transformation in therapeutic medicine.” The same year, President Bill Clinton <a href="https://www.cnn.com/2000/HEALTH/06/26/human.genome.05/index.html">stated</a> the Human Genome Project would “revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases.”</p>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/314040/original/file-20200206-43113-hf9gqo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/314040/original/file-20200206-43113-hf9gqo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/314040/original/file-20200206-43113-hf9gqo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=389&fit=crop&dpr=1 600w, https://images.theconversation.com/files/314040/original/file-20200206-43113-hf9gqo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=389&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/314040/original/file-20200206-43113-hf9gqo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=389&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/314040/original/file-20200206-43113-hf9gqo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=488&fit=crop&dpr=1 754w, https://images.theconversation.com/files/314040/original/file-20200206-43113-hf9gqo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=488&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/314040/original/file-20200206-43113-hf9gqo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=488&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">President Clinton, flanked by J. Craig Venter, left, and Francis Collins, right, announces the completion of a rough draft of the human genome on June 26, 2000.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Associated-Press-Domestic-News-Dist-of-Columbi-/570adf5762e5da11af9f0014c2589dfb/17/0">AP Photo/Rick Bowmer</a></span>
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<p>It is now 2020 and no one carries a genome card. Physicians typically do not examine your DNA to diagnose or treat you. Why not? As I explain in a recent <a href="https://doi.org/10.1080/01677063.2019.1706093">article in the Journal of Neurogenetics</a>, the causes of common debilitating diseases are complex, so they typically are not amenable to simple genetic treatments, despite the hope and hype to the contrary.</p>
<h2>Causation is complex</h2>
<p>The idea that a single gene can cause common diseases has been around for several decades. In the late 1980s and early 1990s, high-profile scientific journals, including Nature and JAMA, announced single-gene causation of <a href="https://doi.org/10.1038/325783a0">bipolar disorder</a>, <a href="https://doi.org/10.1038/336164a0">schizophrenia</a> and <a href="https://doi.org/10.1001/jama.1990.03440150063027">alcoholism</a>, among other conditions and behaviors. These articles drew <a href="https://www.washingtonpost.com/archive/politics/1987/02/26/manic-depression-gene-found/16b6f549-127c-44ed-8b75-75fcf52f60b9/">massive attention</a> in the <a href="https://www.nytimes.com/1990/04/18/us/scientists-see-a-link-between-alcoholism-and-a-specific-gene.html">popular media</a>, but were <a href="https://doi.org/10.1038/342238a0">soon</a> <a href="https://doi.org/10.1038/ng0193-49">retracted</a> <a href="https://doi.org/10.1038/325806a0">or</a> <a href="https://doi.org/10.1038/336167a0">failed</a> <a href="https://doi.org/10.1001/jama.1991.03470130081033">attempts</a> <a href="https://doi.org/10.1001/jama.1993.03500130087038">at</a> <a href="https://doi.org/10.1002/ajmg.1320540202">replication</a>. These reevaluations completely undermined the initial conclusions, which often had relied on <a href="https://doi.org/10.1016/0166-2236(93)90003-5">misguided statistical tests</a>. Biologists were generally aware of these developments, though the follow-up studies received little attention in popular media.</p>
<p>There are indeed individual gene mutations that cause devastating disorders, such as <a href="https://doi.org/10.1038/306234a0">Huntington’s disease</a>. But most common debilitating diseases are not caused by a mutation of a single gene. This is because people who have a debilitating genetic disease, on average, do not survive long enough to have numerous healthy children. In other words, there is strong evolutionary pressure against such mutations. Huntington’s disease is an exception that endures because it typically does not produce symptoms until a patient is beyond their reproductive years. Although new mutations for many other disabling conditions occur by chance, they don’t become frequent in the population. </p>
<p>Instead, most common debilitating diseases are caused by combinations of mutations in many genes, each having a very small effect. They interact with one another and with environmental factors, modifying the production of proteins from genes. The many kinds of microbes that live within the human body can play a role, too. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/314055/original/file-20200206-43079-1u32hbe.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/314055/original/file-20200206-43079-1u32hbe.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/314055/original/file-20200206-43079-1u32hbe.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/314055/original/file-20200206-43079-1u32hbe.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/314055/original/file-20200206-43079-1u32hbe.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/314055/original/file-20200206-43079-1u32hbe.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/314055/original/file-20200206-43079-1u32hbe.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/314055/original/file-20200206-43079-1u32hbe.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A silver bullet genetic fix is still elusive for most diseases.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/little-girl-hospital-91838105">drpnncpptak/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>Since common serious diseases are rarely caused by single-gene mutations, they cannot be cured by replacing the mutated gene with a normal copy, the premise for gene therapy. <a href="https://doi.org/10.1126/science.aan4672">Gene therapy</a> has gradually progressed in research along a very bumpy path, which has included accidentally causing <a href="https://doi.org/10.1016/j.ymthe.2006.03.001">leukemia</a> and <a href="https://doi.org/10.1093/jnci/92.2.98">at least one death</a>, but doctors recently have been successful treating <a href="https://doi.org/10.1126/science.aan4672">some rare diseases</a> in which a single-gene mutation has had a large effect. Gene therapy for rare single-gene disorders is likely to succeed, but must be tailored to each individual condition. The enormous cost and the relatively small number of patients who can be helped by such a treatment may create insurmountable financial barriers in these cases. For many diseases, gene therapy may never be useful.</p>
<h2>A new era for biologists</h2>
<p>The Human Genome Project has had an enormous impact on almost every field of biological research, by spurring technical advances that facilitate fast, precise and relatively inexpensive sequencing and manipulation of DNA. But these advances in research methods have not led to dramatic improvements in treatment of common debilitating diseases. </p>
<p>Although you cannot bring your genome card to your next doctor’s appointment, perhaps you can bring a more nuanced understanding of the relationship between genes and disease. A more accurate understanding of disease causation may insulate patients against unrealistic stories and false promises.</p>
<p>[ <em>You’re smart and curious about the world. So are The Conversation’s authors and editors.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=youresmart">You can read us daily by subscribing to our newsletter</a>. ]</p><img src="https://counter.theconversation.com/content/130568/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ari Berkowitz receives funding from the National Science Foundation.</span></em></p>Genome sequencing technologies have transformed biological research in many ways, but have had a much smaller effect on the treatment of common diseases.Ari Berkowitz, Presidential Professor of Biology; Director, Cellular & Behavioral Neurobiology Graduate Program, University of OklahomaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1296672020-02-10T13:57:50Z2020-02-10T13:57:50ZPotential gene therapy to combat cocaine addiction<figure><img src="https://images.theconversation.com/files/311679/original/file-20200123-162221-1ri4ber.jpg?ixlib=rb-1.1.0&rect=0%2C27%2C4608%2C3421&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">More than 1 million people in the U.S. are addicted to cocaine.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/drugs-addiction-withdrawal-symptoms-concept-depressed-1076759381">Orawan Pattarawimonchai/Shutterstock.com</a></span></figcaption></figure><p>Have you ever slipped when trying to avoid sugar, quit smoking, or break another habit or addiction? Usually that one piece of cake or one cigarette won’t ruin your whole plan, but for people struggling with cocaine addiction, one slip can undo months of hard work. </p>
<p>Cocaine consumption is increasing, with <a href="https://www.samhsa.gov/data/sites/default/files/cbhsq-reports/NSDUHDetailedTabs2017/NSDUHDetailedTabs2017.pdf">2.2 million people in the U.S. admitting to recent cocaine use in 2017</a>. In 2014, the National Survey on Drug Use and Health estimated that nearly 1 million Americans were <a href="https://drugabuse.com/cocaine/relapse/">addicted to cocaine</a>. The effect of cocaine on the brain and body is so powerful that, even after state-of-the-art treatments, <a href="https://drugabuse.com/cocaine/relapse/">many people</a> trying to quit cocaine relapse within a year.</p>
<p>What if cocaine could be made less euphoric, so that a single use by a recovering addict doesn’t result in a full-blown relapse? Scientists at the Mayo Clinic recently published progress toward making this idea a reality – a <a href="https://doi.org/10.1089/hum.2019.233">gene therapy that would treat cocaine addiction</a> by making cocaine less rewarding. </p>
<p>We are a <a href="https://rpmlab.wordpress.com">molecular biologist</a> and a <a href="https://bcmb.utk.edu/people/faculty/rebecca-a-prosser/">neurobiologist</a> who are interested in understanding and treating human disease, including neurological disorders such as cocaine addiction. As University of Tennessee faculty members leading basic biomedical research, we have worked for years on how genes are turned on and off in people and the effects of cocaine on mice, respectively. So, we were excited to see a promising convergence of novel gene therapy and cocaine addiction therapy. </p>
<h2>A treatment to make cocaine less addictive</h2>
<p>Beginning more than 20 years ago, scientists have worked to <a href="https://doi.org/10.1124/mol.55.1.83">engineer a new version of a human protein</a> that could break down cocaine so quickly that it doesn’t produce an addictive high. We all have the normal human protein BChE that helps regulate neurotransmitters, and which can slowly break down cocaine. Targeted mutations in BChE can turn it into a super-CocH – a protein that can quickly break down cocaine. When this CocH is injected into the bloodstream, it breaks down cocaine very fast – before the user can experience the pleasurable effects – so a dose of cocaine is less rewarding. Being less rewarding means it is easier to stop using cocaine. </p>
<p><a href="https://doi.org/10.1124/jpet.108.150029">Previous research</a> has shown that injections of the super-CocH protein drastically decrease addictive behavior in cocaine-addicted rats. That’s great. But the problem is that daily CocH injections would be too expensive and difficult to maintain for the years needed to prevent cocaine relapse for human users. It would be much more practical to provide a single treatment that could provide enough CocH to last for years. </p>
<p>One way to do that is gene therapy: Give patients the DNA sequence (the gene) that contains the instructions for making super-CocH so their bodies can keep making it for months or potentially years. Fortunately, over the past decade, this type of gene therapy has been moving from science fiction to hopeful reality. <a href="https://app.emergingmed.com/asgct/home/:diseaseId%3F/:subDiseaseId%3F">Clinical trials</a> have demonstrated the <a href="https://doi.org/10.1016/j.omtm.2017.11.007">potential of gene therapy to treat diseases</a> from <a href="https://hemophilianewstoday.com/gene-therapy/">hemophilia</a> to <a href="https://doi.org/10.1016/j.neuron.2019.02.01">neurodegenerative disorders</a>, and a handful of these are <a href="https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products">FDA-approved</a>. The <a href="https://doi.org/10.1089/hum.2019.233">new Mayo Clinic study</a> takes an important step toward making CocH gene therapy a reality. </p>
<h2>How does gene therapy work?</h2>
<p>How exactly does a scientist “give a person a gene”? You can’t just swallow DNA the way you would a pill. The Mayo Clinic scientists had to find a way to deliver the gene to every cell in the liver. The way they did this was to insert the gene for super-CocH into a virus called adeno-associated virus (AAV). AAV has been modified so that when it infects cells it cannot reproduce in the body or make someone sick. It is just a delivery vehicle. The virus works by delivering the CocH gene to liver cells, where it remains for months or years. The cells read the super-CocH gene and use it to manufacture many copies of the CocH protein, which then breaks down cocaine. </p>
<p>In the new study, the team tested this approach in mice. The results are very promising and suggest that this gene therapy is safe and effective. Mice receiving the gene therapy alone were healthy. Mice given cocaine became hyperactive and showed signs of liver damage. When the <a href="https://doi.org/10.1089/hum.2019.233">mice were given cocaine plus gene therapy</a> they behaved normally, as if they had not been given the drug. The cocaine was quickly broken down by their new super-CocH proteins, and their livers showed no signs of damage. </p>
<p>The results are promising enough that the FDA has approved plans to proceed with human clinical trials. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/311686/original/file-20200123-162199-1ypurb2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/311686/original/file-20200123-162199-1ypurb2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/311686/original/file-20200123-162199-1ypurb2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/311686/original/file-20200123-162199-1ypurb2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/311686/original/file-20200123-162199-1ypurb2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/311686/original/file-20200123-162199-1ypurb2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=565&fit=crop&dpr=1 754w, https://images.theconversation.com/files/311686/original/file-20200123-162199-1ypurb2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=565&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/311686/original/file-20200123-162199-1ypurb2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=565&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The virus is a delivery vehicle for the gene.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Gene_therapy.jpg">National Institutes of Health</a></span>
</figcaption>
</figure>
<h2>Looking forward</h2>
<p>Keep in mind, this treatment won’t hit the market anytime soon. It took six years from <a href="https://doi.org/10.1371/journal.pone.0067446">initial tests of AAV-CocH therapy in mice</a> to reach the point where the technique is safe enough for human trials. There are many aspects of the treatment that need to be evaluated and modified to make sure it is both safe and effective in humans. </p>
<p>For example, AAV gene therapy can produce <a href="https://doi.org/10.1016/j.omtm.2017.11.007">unwanted immune responses in people</a> that will need to be carefully monitored. Issues such as discomfort caused by the therapy, different responses based on an individual’s genetic makeup and interactions with other medications or medical conditions will also need to be addressed. </p>
<p>Because this study only monitored mice for two months, longer-term effects of the gene therapy will need to be investigated. Also, how well this therapy works to treat cocaine addiction in mice is not really known, and treating addiction in humans is certain to be even more complicated. </p>
<p>This gene therapy could someday make a dose of cocaine less rewarding, but a full recovery from addiction will likely require a combination of treatments administered over many years. </p>
<p>Like many, the two us have family members or friends who struggle with addictions that cannot be cured simply by “trying harder.” This recent work combines careful scientific progress with a creative new idea, giving hope to those trying to overcome cocaine addiction.</p><img src="https://counter.theconversation.com/content/129667/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Rachel Patton McCord receives funding from the National Institute of General Medical Sciences of the National Institutes of Health.</span></em></p><p class="fine-print"><em><span>Rebecca A. Prosser does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Addiction to cocaine is wildly difficult to conquer. But physicians may soon have a new type of gene therapy for patients that makes the drug less alluring.Rachel Patton McCord, Assistant Professor of Biochemistry & Cellular and Molecular Biology, University of TennesseeRebecca A. Prosser, Professor of Biochemistry & Cellular and Molecular Biology, University of TennesseeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1253452019-10-30T12:57:05Z2019-10-30T12:57:05ZSuper-soldier T-cells fight cancer better after a transformational DNA delivery<figure><img src="https://images.theconversation.com/files/298005/original/file-20191021-56194-145vhts.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Delivering DNA to immune cells is the trickiest part of developing new gene-based therapies.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/dna-delivery-logo-icon-design-1020055285?src=tm7y2e5WjiSFAu5jUhfo-A-1-26">SAK Design/SHutterstock.com</a></span></figcaption></figure><p>I enjoy online shopping. However, I often find myself fussing about the delivery options during checkout. This is because not all delivery services are equally efficient and stress-free. </p>
<p>This personal experience has also inspired my research. As a <a href="https://scholar.google.com/citations?user=22Jx6scAAAAJ&hl=en&oi=ao">postdoctoral scholar</a> at <a href="https://www.meloshgroup.com/">Stanford University</a>, I have engineered tiny nano-materials – objects about 10,000 times smaller than a grain of rice – to better deliver DNA into white blood cells called T-cells that defend us against cancer. <a href="https://doi.org/10.1002/adtp.201900133">My method</a> – which I think of as the equivalent of FedEx and UPS – delivers DNA efficiently to T-cells that then transforms them into super-soldiers for tracking and attacking cancer cells. </p>
<h2>The promise of immuno-medicine</h2>
<p>Despite decades of research, cancer remains a challenging disease to treat because cancer cells mutate rapidly, becoming resistant to treatments such as chemotherapeutic drugs and radiation. The World Health Organization estimates that in 2018, <a href="https://www.who.int/news-room/fact-sheets/detail/cancer">close to 10 million individuals died of cancer</a>. The estimated <a href="https://www.who.int/news-room/fact-sheets/detail/cancer">economic cost</a> due to treatments and lost productivity when patients couldn’t work during treatment was a whopping US$1.2 trillion, and this is expected to increase with an aging population.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/297999/original/file-20191021-56211-skkuvh.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/297999/original/file-20191021-56211-skkuvh.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/297999/original/file-20191021-56211-skkuvh.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/297999/original/file-20191021-56211-skkuvh.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/297999/original/file-20191021-56211-skkuvh.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/297999/original/file-20191021-56211-skkuvh.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/297999/original/file-20191021-56211-skkuvh.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/297999/original/file-20191021-56211-skkuvh.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption"></span>
<span class="attribution"><span class="source">Andy Tay</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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</figure>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/297998/original/file-20191021-56207-19z5679.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/297998/original/file-20191021-56207-19z5679.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/297998/original/file-20191021-56207-19z5679.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/297998/original/file-20191021-56207-19z5679.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/297998/original/file-20191021-56207-19z5679.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/297998/original/file-20191021-56207-19z5679.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/297998/original/file-20191021-56207-19z5679.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/297998/original/file-20191021-56207-19z5679.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">These are figurines from a toy kit called ‘Rainbow Heroes.’ I created the kit with the Stanford Design School to educate children with cancer aged 5-10 about cancer immunotherapy. The black figurines represent the ‘enemy’ cancer cells while the colorful figurines are the ‘hero’ immune cells.</span>
<span class="attribution"><span class="source">Andy Tay</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>In the 1990s James Allison and Tasuku Honjo, who won the <a href="https://www.nobelprize.org/prizes/medicine/2018/summary/">2018 Nobel Prize in Medicine or Physiology</a> for cancer immunotherapy, discovered that cancer cells can inhibit T-cells and prevent them from detecting tumor cells. They pioneered a strategy using proteins called antibodies to bind to cancer cells. This prevents the cancer cells from interfering with T-cells and suppressing them.</p>
<p>The second type of cancer immunotherapy, which I study, involves genetically engineering T-cells with tailored DNA. The DNA I insert into T-cells encodes proteins that function like weapons that kill cancer cells faster before they get a chance to develop new mutations.</p>
<p>Unfortunately, it isn’t easy to deliver DNA into cells, and the existing methods are inadequate and may compromise the cancer-fighting functions of T-cells. Some T-cells may become hyperactive after DNA delivery and attack the patients’ own organs.</p>
<h2>Improving DNA delivery</h2>
<p>There are two predominant ways to deliver DNA into T-cells. The first uses viruses to deliver DNA. The second uses bulk electroporation, a technique that uses electricity to punch holes in the cells allowing the DNA to enter. However, both are inefficient and have several disadvantages. </p>
<p>Viruses insert their own viral DNA into host cells alongside the therapeutic DNA during delivery. This is dangerous, as the long-term consequence of having viral genes in our body is unknown. Viruses can also trigger <a href="https://doi.org/10.1016/S0163-7258(98)00020-5">toxic immune responses</a> such as persistent fever and even <a href="https://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html">death</a>. Another disadvantage is that viruses can carry only small packages of DNA, making it difficult to cram the latest gene editing tools inside them. </p>
<p>These shortcomings paved the way for electroporation. This method works by subjecting cells to strong electric fields that create holes in cells’ membrane and allow DNA to pass through. However, this technique is akin to a courier blasting holes in a person’s home to deliver packages. I and others have shown that this approach <a href="https://doi.org/10.1002/adtp.201900133">harms the T-cells</a> and <a href="https://doi.org/10.1073/pnas.1809671115">dampens their cancer-fighting ability</a>. </p>
<h2>The power of nano-engineering</h2>
<p>To bridge this technological gap, <a href="https://doi.org/10.1002/adtp.201900133">I have developed a new technique</a> named magnetic nano-electro-injection, or MagNEI, that can deliver DNA into T-cells up to four times more efficiently than virus and bulk electroporation. This is necessary to produce high numbers of genetically engineered T-cell soldiers – one billion or so – needed to fight cancer. </p>
<p>This is how MagNEI works. I first decorate the T-cells with FDA-approved magnetic particles to activate them and make them more receptive to DNA delivery. Then I use magnets to secure these cells onto hollow nano-tubes. These tubes are 10,000 times smaller in diameter than a grain of rice. Next, electric fields are applied through the nano-tubes to create small pores, or tunnels, into the cell membrane for DNA to enter cells. Magnetic forces then direct DNA into the nucleus of the cell. This is a much gentler procedure than electroporation.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/298974/original/file-20191028-113987-kmkci7.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/298974/original/file-20191028-113987-kmkci7.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/298974/original/file-20191028-113987-kmkci7.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=273&fit=crop&dpr=1 600w, https://images.theconversation.com/files/298974/original/file-20191028-113987-kmkci7.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=273&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/298974/original/file-20191028-113987-kmkci7.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=273&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/298974/original/file-20191028-113987-kmkci7.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=343&fit=crop&dpr=1 754w, https://images.theconversation.com/files/298974/original/file-20191028-113987-kmkci7.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=343&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/298974/original/file-20191028-113987-kmkci7.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=343&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Left: T-cell decorated with magnetic particles that activate it, preparing it for DNA delivery. Right: Scanning electron microscopic image of hollow nano-tubes.</span>
<span class="attribution"><span class="source">Andy Tay</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<h2>New metrics to assess delivery techniques</h2>
<p>Besides looking at DNA delivery efficiency – the percentage of cells that are successfully transformed with genetically engineered DNA – it is also important to consider the other consequences of various delivery methods. For example, I have found that the ability of engineered T-cell soldiers to migrate and hunt down cancer cells can be weaker after DNA delivery. </p>
<p>In my opinion, the cancer immunotherapy community needs to expand beyond simple assessments such as efficiency and cell survival to evaluate the utility of new DNA delivery techniques. </p>
<p>Therefore, in a recent review, <a href="https://doi.org/10.1021/acs.accounts.9b00272">I proposed a framework with new criteria</a> for evaluating which DNA delivery methods are most effective. One way to assess the impact of DNA delivery is to measure how the activity of specific genes are altered by the delivery of foreign DNA. </p>
<p>For instance, I found that bulk electroporation causes significant changes in the activity of genes linked to metabolism. That may explain why cells treated with this method grow slowly. This reduction in cell growth can increase manufacturing costs of these engineered T-cells and lengthen the treatment time for patients. </p>
<p>Magnet-based nano-scale methods such as mine offer advantages over virus and bulk electroporation for DNA delivery, but thus far, I have tested them only in animal studies and in experiments outside of human bodies. In the future, I hope to use nano-materials for delivering DNA to create cell-based therapies.</p>
<p>[ <em>You’re smart and curious about the world. So are The Conversation’s authors and editors.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=youresmart">You can read us daily by subscribing to our newsletter</a>. ]</p><img src="https://counter.theconversation.com/content/125345/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andy Tay does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Researchers are trying to boost the power of our immune system by genetically altering our white blood cells and transforming them into super-soldiers to fight cancer.Andy Tay, Postdoctoral Research Fellow in Materials Science and Engineering, Stanford UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1242622019-10-16T21:57:59Z2019-10-16T21:57:59ZThe blind and visually impaired can help researchers by getting their genes tested<figure><img src="https://images.theconversation.com/files/297399/original/file-20191016-98666-1lztb57.jpg?ixlib=rb-1.1.0&rect=73%2C154%2C4691%2C2906&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Gene therapy trials may mean that the next generation of children born with inherited eye diseases have treatment options.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Blind and partially sighted people no longer have to wait passively for a research breakthrough in hope of treatment options. In fact, people living with genetic eye conditions can now actively drive vision research forward — by enrolling in a patient registry and getting their genes tested.</p>
<p>There are <a href="https://www.who.int/news-room/fact-sheets/detail/blindness-and-visual-impairment#targetText=Globally%2C%20it%20is%20estimated%20that,people%20are%20blind%20(1).">2.2 billion people living with visual impairment globally</a>. Some are living with inherited retinal diseases that are progressive and can lead to complete blindness. Up until recent years, blind and visually impaired people were told that no treatment is available. This is changing as <a href="https://doi.org/10.2174/1566523217666171116170040">genetic testing is paving the way for a surge of gene therapies</a>.</p>
<h2>My passion for vision research is personal</h2>
<p>My <a href="https://doi.org/10.1523/JNEUROSCI.1647-16.2016">doctoral dissertation</a> at the University of British Columbia was on drug therapy for <a href="https://doi.org/10.1016/S0140-6736(06)69740-7">retinitis pigmentosa</a>. This progressive, blinding eye condition is the most common type of inherited retinal disease. </p>
<p>In people affected by retinitis pigmentosa, the light sensing cells in their retina — photoreceptors — die early. Unlike skin cells that regenerate, the body does not make more photoreceptors once they are damaged.</p>
<p>As a vision scientist affected by retinitis pigmentosa, I am passionate about finding the truth about the disease. Why do photoreceptors die? How can we stop it? How can science and medicine help?</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/297405/original/file-20191016-98657-6y043a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/297405/original/file-20191016-98657-6y043a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=371&fit=crop&dpr=1 600w, https://images.theconversation.com/files/297405/original/file-20191016-98657-6y043a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=371&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/297405/original/file-20191016-98657-6y043a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=371&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/297405/original/file-20191016-98657-6y043a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=466&fit=crop&dpr=1 754w, https://images.theconversation.com/files/297405/original/file-20191016-98657-6y043a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=466&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/297405/original/file-20191016-98657-6y043a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=466&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Retinitis pigmentosa causes the light sensing cells, or photoreceptors, in a retina to die early.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
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</figure>
<p>When I was 12 years old, I realized while at summer camp that my night vision was disappearing. In the last two decades, I lost my peripheral vision, contrast sensitivity and depth perception.</p>
<p>I worked in <a href="http://moritzlab.ophthalmology.ubc.ca/">Dr. Orson Moritz’s lab</a> at the UBC department of ophthalmology and visual sciences, which focuses on research using tadpoles that contain known human mutations for retinitis pigmentosa to understand the disease. </p>
<p><a href="https://www.iheart.com/podcast/269-eyes-on-success-rad-29372511/episode/1734-retinitis-pigmentosa-research-aug-16-29372697/">I made an alarming discovery in our animal model</a>: knowing the genetic cause of retinitis pigmentosa is <a href="https://www.jneurosci.org/content/37/4/1039">vital for treatment with one class of drugs — histone deacetylase inhibitors</a>. These determine how genes are switched “on” or “off.”</p>
<p>A similar <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225157/">study in mice</a> showed that the same drug reacted differently to variations in a single mutant gene that also causes retinitis pigmentosa.</p>
<p>Treating retinitis pigmentosa is like extinguishing fire. To stop a fire, you need to know whether it’s water-based or grease-based. If you try to use water to stop a grease fire, the damage gets worse.</p>
<h2>Enrol in a patient registry</h2>
<p>Blind and visually impaired people can advocate for eye health by enrolling in a patient registry. Participation in a registry <a href="https://doi.org/10.1371/journal.pone.0220983">benefits researchers by offering more information</a> about the disease.</p>
<p>In Canada, individuals can self-refer to <a href="https://www.fightingblindness.ca/">Fighting Blindness Canada’s</a> secure, clinical <a href="https://www.fightingblindness.ca/patient-registry/">patient registry</a>. This database is dedicated to connecting people living with retinal eye diseases to clinical trials and research.</p>
<p>When a gene therapy trial arises, researchers draw participants from this database. Since <a href="https://doi.org/10.2174/1566523217666171116170040">gene therapy aims to correct an underlying genetic mistake in DNA that causes disease</a>, knowing the genetic cause of a disease is a criteria for most gene therapy trials.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"897651303010140160"}"></div></p>
<p>Globally, other registries include <a href="https://www.fightingblindness.org/my-retina-tracker">My Retina Tracker</a> in the United States, <a href="https://www.fightingblindness.ie/how-we-can-help/research/target-5000s/">Target 5000</a> in Ireland, <a href="https://myeyesite.org.uk/">MyEyeSite</a> in the United Kingdom, the <a href="https://www.scgh.health.wa.gov.au/Research/DNA-Bank">Australian Inherited Retinal Disease Registry</a> and <a href="http://jegc.org/">Japan Eye Genetics Consortium</a>. In New Zealand, <a href="https://unidirectory.auckland.ac.nz/profile/a-vincent">Dr. Andrea Vincent</a> has established the Genetic Eye Disease Investigation Unit. There is even a <a href="https://www.bcmregistry.org/">Blue Cone Monochromacy Patient Registry</a> for one rare eye condition.</p>
<h2>Blossoming gene therapy trials</h2>
<p>In the last two decades, the number of gene therapy trials has blossomed. Currently, <a href="https://sph.uth.edu/retnet/">250 genes on inherited retinal diseases have been identified</a>. In <a href="http://ir.sparktx.com/news-releases/news-release-details/european-commission-approves-spark-therapeutics-luxturnar#targetText=LUXTURNA%20was%20approved%20by%20the,(%20FDA%20)%20in%20December%202017%20.">2017, the first gene therapy for inherited retinal disease</a> — Luxturna — was <a href="https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna">approved by the United States Federal Drug Administration</a>.</p>
<p>To date, there are trials for: <a href="https://www.clinicaltrials.gov/ct2/results?term=gene+therapy&cond=retinitis+pigmentosa&Search=Apply&recrs=a&age_v=&gndr=&type=&rslt=">retinitis pigmentosa</a>; <a href="https://clinicaltrials.gov/ct2/results?term=Gene+Therapy&cond=Usher&Search=Apply&recrs=a&age_v=&gndr=&type=&rslt=">Usher syndrome</a>, a condition that involves hearing and vision loss;
<a href="https://www.clinicaltrials.gov/ct2/results?term=gene+therapy&cond=Achromatopsia&Search=Apply&recrs=a&age_v=&gndr=&type=&rslt=">achromatopsia</a>, a disease that causes colour blindness; <a href="https://www.clinicaltrials.gov/ct2/results?term=Gene+Therapy&recrs=ab&cond=X-linked+Retinoschisis&rank=1#rowId0%22%22">X-linked retinoschisis</a>, a dystrophy that causes splitting of the retina and affects mostly in males; and <a href="https://www.clinicaltrials.gov/ct2/results?term=gene+therapy&cond=Age+Related+Macular+Degeneration&Search=Apply&recrs=a&age_v=&gndr=&type=&rslt=">age-related macular degeneration</a>, the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2623053/">third-largest cause of vision loss worldwide</a>, caused by the interplay between <a href="https://doi.org/10.1146/annurev-genom-090413-025610">genetics and environment</a>.</p>
<p>Enrolment in a patient registry and genetic testing advance the design of gene therapy trials. This in turn benefits blind and visually impaired people. </p>
<p>Research advancement is a concerted effort across the globe — blind and partially sighted people should know they have the power to push it forward.</p>
<p>[ <em>Like what you’ve read? Want more?</em> <a href="https://theconversation.com/ca/newsletters?utm_source=TCCA&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=likethis">Sign up for The Conversation’s daily newsletter</a>. ]</p><img src="https://counter.theconversation.com/content/124262/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ruanne Vent-Schmidt's doctoral research project was funded by Fighting Blindness Canada.
Ruanne Vent-Schmidt is the Specialist in Peer Support, Advocacy and Research Communications at the Canadian National Institute for the Blind.</span></em></p>Gene therapy trials for inherited retinal diseases are blossoming. Blind and partially sighted people are helping to advance the research.Ruanne Lai, PhD Candidate, Cell & Developmental Biology, University of British ColumbiaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1183292019-06-05T03:30:11Z2019-06-05T03:30:11ZThe gene therapy revolution is here. Medicine is scrambling to keep pace<p><em>This article is an edited extract from Elizabeth Finkel’s address <a href="https://www.npc.org.au/speakers/dr-elizabeth-finkel/">Gene therapy: cure but at what cost?</a> to the National Press Club June 5 2019.</em></p>
<p><em>We’re publishing it as part of our occasional series <a href="https://theconversation.com/au/topics/zoom-out-51632">Zoom Out</a>, where authors explore key ideas in science and technology in the broader context of society and humanity.</em></p>
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<p>Gene therapy – for so long something that belonged to the future – has just hit the streets. </p>
<p>A couple of weeks back, you might have picked up a headline alerting us to the most expensive drug in history – a one off gene therapy cure for spinal muscular atrophy. Novartis have priced the drug <a href="https://www.abc.net.au/news/2019-05-25/worlds-most-expensive-drug-spinal-muscular-dystrophy/11149788">Zolgensma</a> at A$3 million (US$2.1 million).</p>
<p>Traditionally a parent of a baby with spinal muscular atrophy was told: take your baby home and love her or him. Have no false hope, the baby will die paralysed and unable to eat or talk by the age of two. </p>
<p>What’s the narrative going to be now? There is a cure but it costs A$3 million. </p>
<p>I think we are in for some poignant dilemmas. </p>
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Read more:
<a href="https://theconversation.com/boyer-lectures-gene-therapy-is-still-in-its-infancy-but-the-future-looks-promising-104558">Boyer Lectures: gene therapy is still in its infancy but the future looks promising</a>
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<h2>‘Heads up’ from a mother</h2>
<p>The person who gave me a recent “heads up” on the gene therapy revolution was not a scientist. She is the mother of two sick children.</p>
<p>I met Megan Donnell last August 29th at a Melbourne startup conference called “<a href="https://www.bluechilli.com/blog/be-above-all-human/">Above All Human</a>”. </p>
<p>Megan Donnell is a person who strikes you with her vibrancy and charisma.
What you can’t immediately see is her life’s greatest tragedy and her life’s greatest mission.</p>
<p>Both of her children suffer from the rare genetic illness <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664539/">Sanfilippo syndrome</a>. They lack a gene for breaking down heparin sulphate, a sugar that holds proteins in place in the matrix between cells. The high levels of the sugar poison the organs, particularly the brain. In the normal course of the disease, the children die in their teens, paralysed, unable to talk or eat. </p>
<p>When Megan Donnell’s kids were diagnosed at the ages of four and two, she was told “do not have false hope”. <a href="https://www.themonthly.com.au/issue/2019/march/1551445200/elizabeth-finkel/chasing-miracle-gene-therapy">She didn’t listen</a>. </p>
<p>The one time IT business manager started the <a href="https://www.sanfilippo.org.au/">Sanfilippo Childrens’ Foundation</a>, raised a million dollars and invested in a start-up based in Ohio that was trialling gene therapy to treat the disease. Part of the deal was that the company would conduct trials in Australia as well as in the US and Spain. So far 14 children have been treated worldwide. </p>
<h2>I’d missed a revolution</h2>
<p>Megan Donnell’s story stunned me.</p>
<p>I’d written two books about coming medical revolutions: one on stem cells, the other on genomics. But when a medical revolution actually arrived, I’d missed it.
It was all the more remarkable because for six years I’d been the editor of a popular science magazine – <a href="https://cosmosmagazine.com/">Cosmos</a>. </p>
<p>We scanned the media releases for hot papers each week but gene therapy never came up on our radar.</p>
<p>Probably because we’d been dazzled by <a href="https://theconversation.com/what-is-crispr-gene-editing-and-how-does-it-work-84591">CRISPR</a> – the powerful technique that can edit the DNA of everything from mosquitoes to man. But CRISPR has barely entered clinical trials. </p>
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Read more:
<a href="https://theconversation.com/what-is-crispr-gene-editing-and-how-does-it-work-84591">What is CRISPR gene editing, and how does it work?</a>
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<p>Meanwhile there are already five gene therapy products on the market. And with 750 working their way through the pipeline, the US Federal Drug Administration (FDA) predicts that <a href="https://www.technologyreview.com/s/613576/gene-therapy-may-have-its-first-blockbuster/">by 2025 between 10-20 gene therapy treatments</a> will be added to the market each year. </p>
<p>Some of the gene therapies are having incredible effects. </p>
<p>The star example is the <a href="https://www.abc.net.au/news/2019-05-25/worlds-most-expensive-drug-spinal-muscular-dystrophy/11149788">Novartis treatment</a> for spinal muscular atrophy. Untreated babies die paralysed by the age of two. But those treated with Zolgensma have now reached the age of four and some are walking and dancing. </p>
<p>In 2017, the FDA approved <a href="https://www.fda.gov/news-events/press-announcements/fda-approves-novel-gene-therapy-treat-patients-rare-form-inherited-vision-loss">Luxturna</a>, now marketed by Roche. This gene therapy can restore sight to children suffering from a form of retinal blindness that begins months after birth. </p>
<p>For the first time I can recall, medical researchers are using a four letter word for some diseases: cure.</p>
<p>These treatments appear to have fixed the underlying conditions. Especially when they are given early. Indeed spinal muscular atrophy treatment is being offered to babies a few month old – before their motor neurons have started to wither.</p>
<h2>30 years in the making</h2>
<p>These gene therapy treatments have been over thirty years in the making.
And the saga of their journey to the clinic, I suspect, reveals some common plot lines.</p>
<p>The potential of gene therapy, was obvious as soon Marshall Nirenberg cracked the genetic code back in the 1960s. </p>
<p>The <a href="https://profiles.nlm.nih.gov/ps/retrieve/Narrative/JJ/p-nid/24">New York Times opined</a>: “The science of biology has reached a new frontier”, leading to “a revolution far greater in its potential significance than the atomic or hydrogen bomb.”</p>
<p>In a 1967 editorial for Science, <a href="https://science.sciencemag.org/content/sci/157/3789/633.full.pdf">Nirenberg wrote</a>: </p>
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<p>This knowledge will greatly influence man’s future, for man then will have the power to shape his own biological destiny.</p>
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<p>But if the end goal was obvious, the pitfalls were not. </p>
<p>What made the dream of gene therapy possible was viruses. They’ve evolved to invade our cells and sneak their DNA in next to our own, so they can be propagated by our cellular machinery.</p>
<p>Throughout the 1980s, genetic engineers learned to splice human DNA into the viruses. </p>
<p>Like tiny space ships, they carried the human DNA as part of their payload. </p>
<p>By 1990, researchers attempted the first gene therapy trial in a human. It was to treat two children with a dysfunctional immune system, a disease known as severe combined immunodeficiency (<a href="https://www.stanfordchildrens.org/en/topic/default?id=severe-combined-immunodeficiency-scid-90-P01706">SCID</a>). </p>
<p>The results were hardly miraculous but they were promising. Researchers raced to bring more potent viruses to the clinic. </p>
<h2>Children have died</h2>
<p>In 1999, 18 year old <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC81135/">Jesse Gelsinger paid the price</a>.</p>
<p>He had volunteered to try gene therapy for his inherited condition: ornithine transcarbamylase deficiency. It meant he couldn’t break down ammonia, a waste product of dietary protein. But his condition was largely under control through medication and watching his diet.</p>
<p>Four days after his treatment at the University of Pennsylvania, Jesse was dead – a result of a massive immune reaction to the trillions of adenovirus particles introduced into his body. These are the same viruses that cause the common cold. </p>
<p>Tragedy struck again in 2003. This one involved so-called “bubble boys”. </p>
<p>They too carried an immune deficiency, X-SCID, which saw them confined to sterile bubble; a common cold can be fatal. This time round the gene therapy appeared far more effective. But within a few years of treatment, five of 20 boys <a href="https://www.sciencedaily.com/releases/2008/08/080807175438.htm">developed leukaemia</a>. The virus (gamma retrovirus) had activated a cancer-causing gene. </p>
<p>The two tragedies set the field back. Many researchers found it very hard to get funding. </p>
<p>But the huge clinical potential kept others going. </p>
<p>The key was to keep re-engineering the viral vectors. </p>
<p>It was a project that reminds me of the evolution of powered flight. From the biplanes that the Wright brothers flew in 1903 to the epic Apollo 11 flight in 1963, took 60 years.</p>
<p>The virus engineers have been a lot faster.</p>
<h2>Use engineered viruses</h2>
<p>Ten years after the disaster of the leukaemia-causing viruses, researchers had re-engineered so-called <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/lentiviruses">lenti viruses</a> not to activate cancer genes. They had also found other viruses that did not provoke catastrophic immune responses. </p>
<p>Instead of the adenovirus, they discovered its mild-mannered partner – known as adeno associated virus (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548848/">AAV</a>). There’s a whole zoo of these AAVs and some species are particularly good at targeting specific organs.</p>
<p>It is this new generation of vectors that are responsible for the results we are witnessing now. The AAV 9 vector for instance can <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802612/">cross into the brain</a>, and that’s the one used to treat spinal muscular atrophy.</p>
<p>Turning the table on viruses, and hacking into their code: this is the bit that particularly fascinates me in telling the story of gene therapy. </p>
<p>But another intriguing aspect is that, contrary to long held wisdom, we are seeing big pharma galloping in to treat rare diseases.</p>
<p>In the US, the spinal muscular atrophy market is probably around 400 babies per year. Luxturna might treat 2,000 cases of blindness a year. </p>
<p>It’s not the sort of market size that would bring joy to investors. But clearly the companies think it’s worth their while. </p>
<p>For one thing, the FDA has provided incentives for rare, so-called “<a href="https://www.fda.gov/drugs/drug-information-consumers/orphan-products-hope-people-rare-diseases">orphan diseases</a>” – fast-tracking their passage thought the tangled regulatory maze.</p>
<p>And there is a convincing business case. If gene therapy is a one shot cure then it really may end up saving health systems money. </p>
<p>That justifies, they say, some of the most extraordinary prices for a drug you’ve ever heard of. </p>
<p>Of course, all this relies on the treatments being one time cures.</p>
<p>And though the patients seem to be cured, whether or not the treatments last a lifetime remains to be seen. </p>
<h2>The situation in Australia</h2>
<p>Historically, this country has been a world leader when it comes to bargaining down exorbitantly priced cures. </p>
<p>In 2013 when the drugs for curing Hepatitis C first came out, the price was around <a href="https://theconversation.com/weekly-dose-sofosbuvir-whats-the-price-of-a-hepatitis-c-cure-63208">A$100,000 for a 12 week course</a>. But in Australia, <a href="https://theconversation.com/australia-leads-the-world-in-hepatitis-c-treatment-whats-behind-its-success-81760">all 230,000 of those living with Hepatitis C will be treated</a> for the lowest price in the world. Prices are <a href="https://www.healthline.com/health/hepatitis-c/treatment-costs#1">much higher</a> in the US. </p>
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Read more:
<a href="https://theconversation.com/australia-leads-the-world-in-hepatitis-c-treatment-whats-behind-its-success-81760">Australia leads the world in hepatitis C treatment – what's behind its success?</a>
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<p><a href="https://theconversation.com/profiles/greg-dore-190651">Greg Dore</a> at the Kirby Institute of NSW participated in Australia’s Hepatitis C pricing discussions, and believes our model will work for the new gene therapy drugs – notwithstanding their eye-popping price tags – and the fact that the patient populations for these rare genetic diseases will be tiny. </p>
<p>However, the real reason companies are getting into gene therapy is not just to treat rare disease. It’s because they realise this technology will be a game changer for medicine.</p>
<p>They have already entered the field of cancer with a gene therapy approved for acute lymphoblastic leukaemia – CAR-T cells. Health Minister Greg Hunt <a href="https://www.abc.net.au/news/2019-03-25/peter-maccallum-cancer-centre-treatment-funding/10935308">announced this year</a> the government will pay the cost (around A$500,000 per treatment). </p>
<p>But after cancer, what then? </p>
<p>If you have a vector than can take a gene to the brain and cure spinal muscular atrophy, what else could you cure. Alzheimer’s disease, strokes?</p>
<p>Australian researchers are jostling to be part of the gene therapy revolution.</p>
<p>Paediatrician Ian Alexander <a href="https://www.cmri.org.au/Research/Research-Units/Translational-Vectorology/Our-People">together with virologist Leszek Lisowksi</a> are engineering the next generation of vectors in their labs at The Children’s Hospital at Westmead, Sydney. They are designing them to home efficiently to specific organs and produce therapeutic levels of proteins. </p>
<p>Curiously it turns out that a major bottleneck is scaling up the production of these exquisitely engineered viruses. Who’d have thought there’d be a problem churning out the most abundant organism on the planet? </p>
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Read more:
<a href="https://theconversation.com/explainer-how-do-drugs-get-from-the-point-of-discovery-to-the-pharmacy-shelf-78915">Explainer: how do drugs get from the point of discovery to the pharmacy shelf?</a>
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<p>Researcher <a href="https://www.sciencedaily.com/releases/2018/08/180802102344.htm">David Parsons in Adelaide</a> is refining methods to deliver vectors across the viscous mucus of children with cystic fibrosis. </p>
<p>Scientist John Rasko in Sydney is a pioneer when it comes to <a href="https://www.abc.net.au/radionational/programs/breakfast/doctors-find-cure-for-thalassaemia/9674634">treating patients with gene therapy</a>, having been a part of international trials treating patients with beta thalassemia.</p>
<p>Medical researcher Elizabeth Rakoczy in Perth is developing a <a href="https://www.abc.net.au/news/2017-12-06/florey-medal-winner-professor-rakoczy-speaks/9232318">treatment for macular degeneration</a>.</p>
<p>And Alan Trounson, who spent six years at the helm of the world biggest stem cell institute, the California Institute for Regenerative Medicine, is <a href="https://cartherics.com/">advancing a technology</a> to develop off the shelf, universally compatible, CAR-T cells, to attack ovarian cancer. </p>
<p>One thing is for sure: medicine is set for a major disruption from the arrival of gene therapy.</p>
<p>As we enter an era, where once incurable diseases become curable; be prepared for some challenging debates about how to pay for gene therapy and the value of a human life. </p>
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<p><em>This article was amended to correct the spelling of John Rasko’s name.</em></p><img src="https://counter.theconversation.com/content/118329/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Elizabeth Finkel does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>As we enter an era where once incurable diseases become curable, be prepared for some challenging debates about how to pay for gene therapy and the value of a human life.Elizabeth Finkel, Vice-Chancellor's Fellow, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1136272019-03-15T19:19:14Z2019-03-15T19:19:14ZEditing genes shouldn’t be too scary – unless they are the ones that get passed to future generations<figure><img src="https://images.theconversation.com/files/264020/original/file-20190314-28479-o5as8r.jpg?ixlib=rb-1.1.0&rect=0%2C153%2C4268%2C3475&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Gene editing a fertilized human embryo. </span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/gene-editing-science-vitro-genetic-crispr-1263162556">Lightspring/Shutterstock.com</a></span></figcaption></figure><p>Gene editing is one of the <a href="https://theconversation.com/how-a-scientist-says-he-made-a-gene-edited-baby-and-what-health-worries-may-ensue-107764">scarier things in the science news</a>, but not all gene editing is the same. It matters whether researchers edit “somatic” cells or “germline” cells. </p>
<p>Germline cells are the ones that propogate into an entire organism – either cells that make sperm and eggs (known as germ cells), or the cells in an early embryo that will later differentiate into different functions. What’s critical about those particular cells is that a change or mutation in one will go on to affect every cell in the body of a baby that grows from them. That’s why scientists are calling for a <a href="http://doi.org/10.1038/d41586-019-00788-5">moratorium on editing the genes of germ cells or germline cells</a>. </p>
<p>Somatic cells are everything else – cells in particular organs or tissues that perform a specific function. Skin cells, liver cells, eye cells and heart cells are all somatic. Changes in somatic cells are much less significant than changes in germline cells. If you get a mutation in a liver cell, you may end up with more mutant liver cells as the mutated cell divides and grows, but it will never affect your kidney or your brain.</p>
<p>Our bodies accumulate mutations in somatic tissues throughout our lives. Most of the time humans never know it or suffer any harm. The exception is when one of those somatic mutations grows out of control leading to cancer.</p>
<p>I am a <a href="http://www.publichealth.pitt.edu/home/directory/eleanor-feingold">geneticist</a> who studies the genetic and environmental causes of a number of different disorders, from birth defects – <a href="https://doi.org/10.1371/journal.pgen.1007501">cleft lip and palate</a> – to diseases of old age like <a href="https://doi.org/10.1038/s41380-018-0246-7">Alzheimer’s</a>. Studying the genome always entails thinking about how the knowledge you generate will be used, and whether those likely uses are ethical. So geneticists have been following the gene editing news with great interest and concern.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/264019/original/file-20190314-28512-gztrol.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/264019/original/file-20190314-28512-gztrol.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/264019/original/file-20190314-28512-gztrol.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=360&fit=crop&dpr=1 600w, https://images.theconversation.com/files/264019/original/file-20190314-28512-gztrol.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=360&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/264019/original/file-20190314-28512-gztrol.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=360&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/264019/original/file-20190314-28512-gztrol.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=452&fit=crop&dpr=1 754w, https://images.theconversation.com/files/264019/original/file-20190314-28512-gztrol.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=452&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/264019/original/file-20190314-28512-gztrol.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=452&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Germ cells are the cells - egg and sperm - that make a baby. Editing genes in these cells will cause permanent changes in the child and all of their progeny.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/structure-human-gametes-ovum-sperm-cell-496197304">arborelza/Shutterstock.com</a></span>
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<p>In gene editing, it matters enormously whether you are messing with a germline cell, and thus an entire future human being and all its future descendants, or just one particular organ. Gene therapy – fixing faulty genes in individual organs – has been one of the <a href="https://onlinelibrary.wiley.com/doi/full/10.1002/jgm.3015">great hopes</a> of medical science for decades. There have been a few successes, but more failures. Gene editing may make gene therapy more effective, potentially curing important diseases in adults. The National Institutes of Health runs a well-respected and highly ethical <a href="https://commonfund.nih.gov/editing">research program</a> to develop tools for safe and effective gene editing to cure disease.</p>
<p>But editing germline cells and creating babies whose genes have been manipulated is a very different story, with multiple ethical issues. The first set of concerns is medical – at this point society doesn’t know anything about the safety. “Fixing” the cells in the liver of someone who might otherwise die of liver disease is one thing, but “fixing” all of the cells in a baby who is otherwise healthy is a much higher-risk proposition. This is why the recent announcement that a Chinese scientist had done just that created such an uproar.</p>
<p>But even if we knew the procedure was safe, gene editing of the germline would still catapult us straight into all of the “designer baby” controversies and the problems of creating a world where people try to micromanage their offspring’s genes. It does not take much imagination to fear that gene editing will could bring us a new era of eugenics and discrimination. </p>
<p>Does gene editing still sound scary? It should. But it makes a big difference whether you are manipulating individual organs or whole human beings.</p><img src="https://counter.theconversation.com/content/113627/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Eleanor Feingold does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Scientists worldwide are calling for a moratorium on gene editing in germline cells. But what is a germline cell? How does it differ from other cells in our body? Why does it matter if we edit them?Eleanor Feingold, Professor, Departments of Human Genetics and Biostatistics, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1031652018-10-15T04:56:44Z2018-10-15T04:56:44ZBoyer Lectures: the new eugenics is the same as the old, just in fancier clothes<figure><img src="https://images.theconversation.com/files/240531/original/file-20181015-109242-9qjj2o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Eugenics was previously the realm of social biology.</span> <span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Eugenics_Quarterly_to_Social_Biology.jpg">Wikimedia Commons</a></span></figcaption></figure><p><em>This year marks the 60th anniversary of the ABC’s Boyer Lectures. Delivered by Professor John Rasko, the 2018 <a href="http://about.abc.net.au/press-releases/life-re-engineered-abc-boyer-lectures-explore-how-gene-therapy-will-change-what-it-means-to-be-human/">Life Engineered</a> lectures explore ethical and other issues around gene therapy and related technologies, and their potential to cure disease, prolong life and change the course of human evolution.</em> </p>
<p><em>The first lecture will be broadcast on RN’s Big Ideas at 8pm tonight. In this article, we explore the history of eugenics and the ethical implications of its resurgence with the evolution of genetic therapy.</em></p>
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<p>News about the potential of genetic engineering to improve our lives is often compromised by problematic stories about its potential for misuse. Should couples be allowed to choose the gender of their offspring? Should the state intervene in the reproductive lives of its citizens?</p>
<p>We can see this most recently in the <a href="https://www.smh.com.au/national/australian-parents-flock-to-us-clinics-to-choose-baby-s-gender-20180823-p4zzdu.html">case of couples travelling</a> to clinics overseas to use IVF to choose the gender of their child – a practice prohibited in Australia. Such case studies represent only the current point in a long history of the debate about “improving” humanity – the science of eugenics.</p>
<p>Some <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135459/">scientists and ethicists believe</a> eugenics is a value-free science that got a bad name due to the practices in Nazi Germany. </p>
<p>Philosopher and bioethicist Julian Savulescu, for instance, has <a href="http://www.abc.net.au/radionational/programs/earshot/is-this-the-new-eugenics/7578480">endorsed</a> the “new eugenics”, claiming that in its previous incarnation it was sullied by bad science and state intervention. He has argued we have a moral obligation to <a href="https://ideas.ted.com/the-ethics-of-genetically-enhanced-monkey-slaves/">overcome some limitations</a> if science permits it, such as ensuring babies aren’t born with certain types of disabilities.</p>
<p>The argument follows that the new science is “good” science and the free market will lead to human improvement, not contravene fundamental rights.</p>
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Read more:
<a href="https://theconversation.com/toby-young-what-is-progressive-eugenics-and-what-does-it-have-to-do-with-meritocracy-89671">Toby Young: what is 'progressive eugenics' and what does it have to do with meritocracy?</a>
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<h2>Eugenics not a Nazi creation</h2>
<p>Discussing Nazi eugenics, however, misses the point. This is because German eugenicists actually learnt the craft from observing the <a href="http://www.pbs.org/independentlens/blog/unwanted-sterilization-and-eugenics-programs-in-the-united-states/">extensive sterilisation programs</a> in the US in the 1920s and ’30s that stopped tens of thousands of people from reproducing. </p>
<p>Legal oversight failed completely. The sterilisation program that targeted “inferior” Americans was endorsed by the Supreme Court in <a href="https://en.wikipedia.org/wiki/Buck_v._Bell">Buck v Bell in 1927</a>. Carrie Buck was surgically sterilised at the age of 22 using fabricated evidence of her, her mother’s and her seven-month-old daughter’s mental incapacity. The reason given in the leading judgment was that “three generations of imbeciles is enough”.</p>
<p>The <a href="https://historynewsnetwork.org/article/1796">Rockefeller Foundation funded</a> the pre-second world war work of Josef Mengele (a doctor who later performed human experiments on prisoners at Auschwitz concentration camp) on <a href="http://journals.sagepub.com/doi/abs/10.2190/B7UY-N2UM-6R4G-XPCF">genetics and disease</a>. Along with the Carnegie Foundation and the Harriman family, millions of dollars went into research programs used to justify the sterilisation of people in the US with <a href="https://historynewsnetwork.org/article/1796">disabilities</a>. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/240529/original/file-20181015-109239-sd7lel.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/240529/original/file-20181015-109239-sd7lel.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/240529/original/file-20181015-109239-sd7lel.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=373&fit=crop&dpr=1 600w, https://images.theconversation.com/files/240529/original/file-20181015-109239-sd7lel.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=373&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/240529/original/file-20181015-109239-sd7lel.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=373&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/240529/original/file-20181015-109239-sd7lel.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=468&fit=crop&dpr=1 754w, https://images.theconversation.com/files/240529/original/file-20181015-109239-sd7lel.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=468&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/240529/original/file-20181015-109239-sd7lel.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=468&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">The US sterilised tens of thousands of people with disabilities in the early 20th century.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/Compulsory_sterilization#/media/File:SOU_1929_14_Bet%C3%A4nkande_med_f%C3%B6rslag_till_steriliseringslag_s_57_Laughlin.jpg">(taken from1929 Swedish royal commission report) Wikimedia Commons</a></span>
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<h2>Leading scientists and eugenics</h2>
<p>Not that we can point the finger just at the US. Charles Darwin’s cousin <a href="http://www.galtoninstitute.org.uk/">Francis Galton</a> founded the modern eugenics movement in Britain. He set the ball in motion for the <a href="http://eugenicsarchive.ca/discover/tree/5233e5175c2ec500000000e1">Eugenics Society</a> to be born in the early 1900s. It supported policies that reduced the breeding rights of “inferior” members of society – ranging from birth-control clinics in the slums of major cities and severe restrictions on immigration, through to state-imposed sterilisation.</p>
<p>The first Galton Chair of Eugenics at University College London, Karl Pearson, discovered many of the most important principles underlying modern statistics. Central to his development of statistics was his work in <a href="https://en.wikipedia.org/wiki/Karl_Pearson#Politics_and_eugenics">establishing methods of measuring biological normality</a> for the purposes of breeding “better” humans. </p>
<p>Many leading biological scientists and Nobel laureates were members of the society – the brightest minds of generations, who were thought leaders of the time. These included Ronald Fisher, the founder of modern evolutionary biology (who argued that the poorer classes are genetically inferior to the middle classes), the Nobel Prize-winning immunologist Peter Medawar and IVF pioneer Robert Edwards. </p>
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Read more:
<a href="https://theconversation.com/boyer-lectures-gene-therapy-is-still-in-its-infancy-but-the-future-looks-promising-104558">Boyer Lectures: gene therapy is still in its infancy but the future looks promising</a>
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<p>Leading scientists still preached the eugenic message of the biological inequality of humans after 1945, as well as the need to restrict the reproductive rights of such people. For example, in the late 1950s and early 1960s Australia’s own Nobel laureate, virologist McFarlane Burnett, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2973702/">pointed</a> out the danger in letting less intelligent members of society have larger families in an article of the Eugenics Society magazine, the Eugenics Review. </p>
<p>Even more controversially, James Watson, who with Francis Crick and, with a very belated acknowledgement, Rosalind Franklin, discovered the double-helix architecture of the chromosome in 1953, argued recently that blacks are less genetically intelligent than <a href="https://blogs.scientificamerican.com/news-blog/james-watson-and-eugenics/">whites</a>, and that women are less able in the sciences. </p>
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Read more:
<a href="https://theconversation.com/eugenics-in-australia-the-secret-of-melbournes-elite-3350">Eugenics in Australia: The secret of Melbourne's elite</a>
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<h2>But we’re ‘better’ now</h2>
<p>Maybe the science is much “better” now, as <a href="https://theconversation.com/science-is-in-a-reproducibility-crisis-how-do-we-resolve-it-16998">Savalescu claims</a> – but there have been <a href="https://theconversation.com/heres-what-we-know-about-crispr-safety-and-reports-of-genome-vandalism-100231">concerns</a> about that as well. </p>
<p>Perhaps the most important consideration when evaluating the benefits of the new eugenics is the vexed question of what makes a human “better”.</p>
<p>Certainly if we take deafness, there is an important movement of the deaf that sees deafness as a <a href="http://dsq-sds.org/article/view/344/435">culture</a>, not a <a href="https://www.theguardian.com/world/2002/apr/08/davidteather">disability</a>. Advocates of this view argue that deaf people aren’t lacking in a way that makes them inferior, they are just different and society should accommodate such difference, not “cure” it, in the same way homosexuality has been de-medicalised.</p>
<p>Can this be said of other so-called disabilities? Is having a higher IQ “better”? </p>
<p>The founder of social Darwinism, Herbert Spencer, coined the term “survival of the fittest”. Interrogating this statement actually shows its a tautology. </p>
<blockquote>
<p>Question: Who survives? </p>
<p>Answer: The fittest</p>
<p>Question: Who are the fittest? </p>
<p>Answer: Those who survive.</p>
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<p>A tautology is a meaningless formula for future action as it only describes what has gone on in the past. We know who “survived”, it’s the story written by the “winners”. For Spencer, middle-class white males were the “fittest”. Have we just replaced “fittest” with “best”? </p>
<p>We need to think clearly about the consequences of the new genetic technologies and not blindly embrace them in the name of “betterment” if we don’t scrupulously interrogate why such “improvements” are necessary. This was a problem with most of the <a href="https://en.wikipedia.org/wiki/Naturalistic_fallacy">definitions</a> of the unfit by eugenicists in the past. </p>
<p>If significant <a href="https://www.smh.com.au/business/the-economy/the-social-sciences-so-essential-we-neglect-them-20180909-p502nq.html">funding</a> is to be allocated to the modern eugenics, policymakers must be involved in finding solutions to these problems, otherwise the “new eugenics” is just the old one in new clothes.</p><img src="https://counter.theconversation.com/content/103165/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ross L Jones has received funding from the ARC. </span></em></p>If those who survive are the fittest, does that also make them the best? And if so, is engineering ‘better’ babies just evolution, or another step in a long history of eugenics?Ross L Jones, Honorary Senior Fellow, Department of Anatomy and Neuroscience, University of Melbourne; Associate, Centre for Health Law and Society, La Trobe University, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1045582018-10-14T19:06:40Z2018-10-14T19:06:40ZBoyer Lectures: gene therapy is still in its infancy but the future looks promising<figure><img src="https://images.theconversation.com/files/240370/original/file-20181012-119132-1l8k67h.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Determining the structure of the DNA was the beginning of the gene therapy journey.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p><em>This year marks the 60th anniversary of the ABC’s Boyer Lectures. Delivered by Professor John Rasko, the 2018 <a href="http://about.abc.net.au/press-releases/life-re-engineered-abc-boyer-lectures-explore-how-gene-therapy-will-change-what-it-means-to-be-human/">Life Engineered</a> lectures explore ethical and other issues around gene therapy and related technologies, and their potential to cure disease, prolong life and change the course of human evolution.</em> </p>
<p><em>The first lecture will be broadcast on RN’s <a href="http://www.abc.net.au/radionational/programs/bigideas/">Big Ideas</a> at 8pm tonight. In light of this, we’ve asked Merlin Crossley to explain what gene therapy actually is and how we got to where we are with it.</em></p>
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<p>Over the last few centuries, infectious diseases have been understood and tackled, through advances in sanitation, anti-microbial medications and vaccination. One day we may also be able to tackle genetic diseases – lifelong conditions arising from mutations that we inherit from our ancestors or that occur during our development.</p>
<p>We’re over the foothills but we still have mountains to climb in treating genetic diseases.</p>
<h2>Step 1 – understanding genetic disease</h2>
<p>The key step to tackling infectious diseases was to truly define the nature of the microorganisms that caused them. Similarly, with genetic diseases the first step was to understand and define the nature of a gene. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=424&fit=crop&dpr=1 600w, https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=424&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=424&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=533&fit=crop&dpr=1 754w, https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=533&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=533&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Our red blood cells carry oxygen with the help of the protein haemoglobin.</span>
<span class="attribution"><span class="source">shutterstock.com</span></span>
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<p>Scientists, including Watson, Crick and Franklin, <a href="https://www.sciencehistory.org/historical-profile/james-watson-francis-crick-maurice-wilkins-and-rosalind-franklin">determined the structure of DNA</a> in 1953. Gradually it became clear that a gene was a stretch of DNA that encoded a functional product, such as the oxygen-carrying protein haemoglobin. </p>
<p>Around the same time in 1949, US chemist <a href="https://www.britannica.com/biography/Linus-Pauling">Linus Pauling demonstrated</a> that the disease sickle cell anaemia was caused by a chemical change in haemoglobin. He called this the first “molecular disease”. With the advent of DNA sequencing in the 1970s, the <a href="https://ghr.nlm.nih.gov/gene/HBB">actual mutation</a> in the globin gene was identified. </p>
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Read more:
<a href="https://theconversation.com/explainer-one-day-science-may-cure-sickle-cell-anaemia-28153">Explainer: one day science may cure sickle cell anaemia</a>
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<p>Rapidly after this, the genetic lesions responsible for other inherited diseases – such as haemophilia, cystic fibrosis and muscular dystrophy – were identified. From this moment on, the idea of replacing defective genes or correcting them captured people’s imaginations, and this is the basis of what we now call “gene therapy”.</p>
<h2>Step 2 – replacing defective genes</h2>
<p>Patients suffering from genetic diseases either have a defective gene or may altogether lack a key gene. In the early stages of gene therapy there was no way of correcting genes, so researchers focused on supplementing the body with a replacement gene. </p>
<p>In the 1980s, recombinant DNA technology (where chosen DNA molecules are transferred between individual organisms) was developed by harnessing the miniature machinery bacteria and viruses use to move DNA around. This allowed researchers to isolate individual human genes and encapsulate them in harmless viruses to deliver them into human cells.</p>
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<a href="https://images.theconversation.com/files/240366/original/file-20181012-119138-1864f24.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/240366/original/file-20181012-119138-1864f24.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/240366/original/file-20181012-119138-1864f24.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=303&fit=crop&dpr=1 600w, https://images.theconversation.com/files/240366/original/file-20181012-119138-1864f24.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=303&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/240366/original/file-20181012-119138-1864f24.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=303&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/240366/original/file-20181012-119138-1864f24.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=381&fit=crop&dpr=1 754w, https://images.theconversation.com/files/240366/original/file-20181012-119138-1864f24.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=381&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/240366/original/file-20181012-119138-1864f24.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=381&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">In somatic gene therapy, the therapeutic genes can be put inside a virus and transported into the body.</span>
<span class="attribution"><span class="source">shutterstock.com</span></span>
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<p>It was possible to get the genes into certain blood cells and other accessible tissues. This process was termed somatic gene therapy (from “soma” meaning, “the body”) and was distinct from <a href="https://www.genome.gov/10004764/germline-gene-transfer/">germline gene therapy</a> where eggs or sperm, or early embryos, would be modified and whole people and their offspring changed forever. </p>
<p>Human germline gene therapy is widely outlawed and there is no evidence it has ever been seriously attempted.</p>
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Read more:
<a href="https://theconversation.com/human-genome-editing-report-strikes-the-right-balance-between-risks-and-benefits-72951">Human genome editing report strikes the right balance between risks and benefits</a>
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<p>But <a href="https://www.ncbi.nlm.nih.gov/pubmed/8976157">somatic gene therapy</a> has been attempted and, in some cases, has been successful. Viruses really can be made harmless and filled with human DNA, which they deliver into the patient’s cells. </p>
<p>A handful of people have now been successfully treated in this way for <a href="https://presse.inserm.fr/en/new-gene-therapy-success-in-beta-thalassemia-22-patients-treated-in-france-united-states-thailand-and-australia/31149/">haemoglobin deficiencies</a>, <a href="https://www.haemophilia.org.au/publications/national-haemophilia/2018/no-201-march-2018/gene-therapy">haemophilia</a>, and for immune disorders, such as so-called <a href="https://www.webmd.com/baby/news/20171209/gene-therapy-may-be-cure-for-bubble-boy-disease#1">“bubble boy” disease </a> (where victims are particularly vulnerable to infectious diseases).</p>
<h2>Step 3 – improving replacement gene therapy</h2>
<p>Attempts at these forms of gene replacement therapy began in the 1990s but <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681190/">early results</a> were disappointing. It proved difficult to get the genes into enough human cells, and when the genes did get in they were often <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC289175/">turned off</a> after a few weeks.</p>
<p>More worryingly, it was not possible to determine where in the chromosome the replacement gene would land. Often it integrated harmlessly in an unimportant part of the genome, but sometimes it landed near to, and activated, growth control genes called “oncogenes” that drive cellular proliferation and cancer. </p>
<p>Some of the <a href="https://www.newscientist.com/article/dn2878-miracle-gene-therapy-trial-halted/">first children treated</a> for “bubble boy” disease developed leukemias. These leukemias were treatable, but the complications, together with immune reactions, such as led to the death of <a href="https://en.wikipedia.org/wiki/Jesse_Gelsinger">Jesse Gelsinger</a> in an early gene therapy trial in 2000, led to caution.</p>
<p>Over the years, researchers have developed better viruses, systematically improved the gene delivery protocols and found control switches that aren’t turned off by our body’s anti-viral response. In recent gene therapy trials for <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1708538">haemophilia</a>, <a href="http://www.bloodjournal.org/content/130/Suppl_1/355?sso-checked=true">haemoglobin</a> disorders, and also for specific inherited forms of <a href="https://mashable.com/2018/03/24/gene-therapy-blindness-treatment/">blindness</a>, many of the patients treated have benefited.</p>
<h2>Step 4 – gene correction</h2>
<p>The advent of new techniques, most notably CRISPR-mediated gene editing, has led to the idea of correcting a mutant gene rather than adding a replacement. CRISPR is a system that bacteria use to identify and cut invading viral DNA. It has now been used by researchers to direct DNA modification machines to chosen human genes. </p>
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<p>We can now develop miniature chemical tools to convert harmful mutations back into normal sequences. News that this technology was being used on <a href="https://link.springer.com/article/10.1007%2Fs13238-015-0153-5">human embryos in China</a> created a storm of controversy but so far those experiments have only involved embryos that were known to be non-viable and the research has been purely experimental.</p>
<p>Elsewhere researchers aren’t exploring modifications of whole embryos. Instead the somatic gene therapy approach is being followed, for example, to see if genes can be corrected in a high proportion of <a href="https://www.sciencedirect.com/science/article/pii/S1525001616453323">blood stem cells</a> and whether these cells can then be transplanted back into the patient to cure their disease.</p>
<h2>Step 5 – The future</h2>
<p>We will soon see an increasing number of patients helped by both gene replacement therapy and by CRISPR-mediated gene correction. But the work is likely to be focused on a few specific diseases rather than there being a broad advance across all genetic diseases. </p>
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<a href="https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=629&fit=crop&dpr=1 600w, https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=629&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=629&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=791&fit=crop&dpr=1 754w, https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=791&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=791&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">An increasing number of patients will soon be helped by CRISPR-mediated gene correction.</span>
<span class="attribution"><span class="source">shutterstock.com</span></span>
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<p>The diseases treated first will share some key characteristics: the genetic defects would be well-understood; they must affect a tissue we can get at easily (blood will be easier than brains and bones); the conditions would be serious and have no other effective treatments. </p>
<p>And they must be so costly in terms of human suffering and economic burdens that a complex and expensive treatment such as gene therapy becomes a viable option. </p>
<p>This means common blood and immune disorders are likely to feature in the first generation trials. Cancer is also a genetic disease, but one typically caused by mutations that accumulate in our cells over time rather than by inherited mutations, and somatic gene therapy, in the form of immunotherapy, involving enhancing the capacity of our immune systems to fight cancer may also become common. </p>
<p>A Nobel Prize was <a href="https://www.nytimes.com/2018/10/01/health/nobel-prize-medicine.html">just awarded</a> for anti-cancer immunotherapy, and it is likely that the genetic modification of the immune system will increasingly be used to treat cancers.</p>
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Read more:
<a href="https://theconversation.com/how-two-1990s-discoveries-have-led-to-some-cured-cancers-and-a-nobel-prize-104221">How two 1990s discoveries have led to (some) cured cancers, and a Nobel Prize</a>
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<p>The age of gene therapy is arriving but it will be gradual, not sudden. But incrementally, more people will benefit from these treatments. </p>
<p>In the long term, as we all become aware of mutations we carry in our own genomes that may affect our offspring, there may be pressure to correct more and more genetic lesions. This will remain too risky and expensive for many years so gene therapy will likely remain a niche and specialist treatment for the foreseeable future.</p><img src="https://counter.theconversation.com/content/104558/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Merlin Crossley works for UNSW and receives funding from the Australian Research Council and National Health and Medical Research Council, and serves on the Trust of the Australian Museum, the Australian Science Media Centre, UNSW Press, UNSW Global, and is on the Editorial Board of The Conversation and of he journal Bioessays. </span></em></p>Once genetic lesions for diseases such as cystic fibrosis and haemophilia were identified, the idea of replacing or correcting defective genes grew into what we now call “gene therapy”.Merlin Crossley, Deputy Vice-Chancellor Academic and Professor of Molecular Biology, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1032232018-09-17T16:09:58Z2018-09-17T16:09:58ZResearchers block cocaine craving and addiction with a special skin graft<figure><img src="https://images.theconversation.com/files/236496/original/file-20180915-177938-mvaqnw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Lines of cocaine.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/rolled-bill-snorting-drug-powder-illegal-332146472?src=hJYWAPBjFUh60CNHA9TAiA-1-5">Christopher Slesarchik/Shutterstock.com</a></span></figcaption></figure><p>Addiction to any drug – be it alcohol, tobacco, opioids or illicit drugs, like cocaine – is a chronic disease that causes a compulsive drug-seeking behavior individuals find difficult or impossible to control even when they are aware of the harmful, often deadly consequences. </p>
<p>Long-term use changes the structure of brain regions linked to judgment, stress, decision-making and behavior, making it increasingly difficult to ignore drug cravings. </p>
<p>I am a postdoctoral researcher in the <a href="https://anesthesia.uchicago.edu/page/ming-xu-laboratory">laboratory of Ming Xu</a> at the University of Chicago, where we study addiction, with a goal of finding an effective cure. <a href="https://www.nature.com/articles/s41551-018-0293-z">In a paper in Nature Biomedical Engineering</a>, we describe a new approach, which we developed and tested, that blocks cocaine-seeking in mice and actually protects them from high doses that would otherwise be deadly.</p>
<h2>How can gene therapy stop addiction?</h2>
<p>Present in human liver and blood is a natural enzyme called butyrylcholinesterase, which we abbreviate as BChE. One of this enzyme’s jobs is to break down, or metabolize, cocaine into inactive, harmless components. In fact, there is even a <a href="http://doi.org/10.1038/ncomms4457">mutant human BChE</a> (hBChE), which was genetically engineered to greatly accelerate the metabolism of cocaine. This super mutant enzyme is expected to become a <a href="http://doi.org/10.1124/jpet.113.206383">therapy</a> for treating cocaine addiction. However, delivering the active enzyme to addicts by injection and keeping this enzyme functioning in living animals is challenging. </p>
<p>So instead of giving the enzyme to the animals, we decided to engineer skin stem cells that carried the gene for the BChE enzyme. This way the skin cells would be able to manufacture the enzyme themselves and supply the animal. </p>
<p><a href="https://www.nature.com/articles/s41551-018-0293-z">In our study</a>, we first used the gene-editing technique CRISPR to edit the mouse skin stem cells and incorporate the hBChE gene. These engineered skin cells produced consistent and high levels of the hBChE protein, which they then secreted. Then we grew these engineered stem cells in the lab and created a flat layer of skin-like tissue which took a few days to grow.</p>
<p>Once the lab-grown skin was complete, we transplanted it into host animals where the cells released significant quantities of hBChE into blood for more than 10 weeks. </p>
<p>With the genetically engineered skin graft releasing hBChE into the blood stream of the host mice, we hypothesized that if the mouse consumed cocaine, the enzyme would rapidly chop up the drug before it could trigger the addictive pleasure response in the brain.</p>
<h2>‘Immunizing’ against cocaine</h2>
<p>Cocaine works by elevating dopamine levels in the brain which then result in feelings of reward and euphoria, which trigger a craving for more of the drug.</p>
<p>The animals that received the engineered skin graft were able to clear injected quantities of cocaine faster than control animals. Their brains also had lower levels of dopamine. </p>
<p>Moreover, the skin grafts of hBChE-producing cells can effectively decrease the rate of lethal overdoses from 50 percent to zero when the animals were injected with a high, potentially lethal, dose of cocaine. When animals were given a lethal dose, all the control animals died while none of the animals that received the engineered skin perished. It was as if the enzyme produced by the skin graft had immunized the mice against a cocaine overdose.</p>
<p>We then assessed whether hBChE-producing cells can protect against development of cocaine-seeking. We used mice that were trained to reveal their preference for cocaine by spending more time in a cocaine-rich environment. Under the same dosage and training procedures, normal animals acquired preference to cocaine, whereas host animals with the skin graft showed no such preference, indicating skin graft of the hBChE-cells efficiently blocks the cocaine-induced reward effect. In a similar way, skin-derived hBChE efficiently and specifically disrupts recurrence of cocaine-seeking after 25 days of withdrawal.</p>
<p>To test whether this gene therapy approach will work in humans, we grew human skin-like tissue from primary skin stem cells that were genetically edited by CRISPR to allow hBChE production. </p>
<p>We were encouraged to see that engineered human epidermal cells produced large quantities of hBChE in cells cultured in the lab and in mice. This suggests the concept of skin gene therapy may be effective for treating cocaine abuse and overdose in humans in the future.</p>
<p>Adapting this approach for humans could be a promising way for blocking addiction. But first we must have sufficient evidence that it works well with few side effects. Likewise, engineering skin cells with the enzymes that degrade alcohol and nicotine could be an effective strategy for curbing addiction and abuse of these two drugs as well.</p><img src="https://counter.theconversation.com/content/103223/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Qingyao Kong does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>In a completely new approach to treating addiction, researchers use genetically engineered skin cells to inactivate cocaine and block cravings and addiction in mice.Qingyao Kong, Postdoctoral researcher in the Department of Anesthesia & Critical Care, University of ChicagoLicensed as Creative Commons – attribution, no derivatives.