Category Archives: Genetic Therapy

Gerald Maguire has stuttered since childhood, but you might not guess it from talking to him. For the past 25 years, Maguire a psychiatrist at the University of California, Riverside has been treating his disorder with antipsychotic medications not officially approved for the condition. Only with careful attention might you discern his occasional stumble on multisyllabic words like statistically and pharmaceutical.

Maguire has plenty of company: More than 70 million people worldwide, including about 3 million Americans, stutter that is, they have difficulty with the starting and timing of speech, resulting in halting and repetition. That number includes approximately 5 percent of children, many of whom outgrow the condition, and 1 percent of adults. Their numbers includepresidential candidate Joe Biden,deep-voiced actor James Earl Jonesand actressEmily Blunt. Though those people and many others, including Maguire, have achieved career success, stuttering can contribute to social anxiety and draw ridicule or discrimination by others.

Maguire has been treating people who stutter, and researching potential treatments, for decades. He receives daily emails from people who want to try medications, join his trials, or even donate their brains to his university when they die. Hes now embarking on a clinical trial of a new medication, called ecopipam, that streamlined speech and improved quality of life in a small pilot study in 2019.

Others, meanwhile, are delving into the root causes of stuttering, which also may point to novel treatments. In past decades, therapists mistakenly attributed stuttering to defects of the tongue and voice box, to anxiety, trauma or even poor parenting and some still do. Yet others have long suspected that neurological problems might underlie stuttering, says J. Scott Yaruss, a speech-language pathologist at Michigan State University in East Lansing. The first data to back up that hunch came in 1991, Yaruss says, when researchers reportedaltered blood flow in the brains of people who stuttered. Over the past two decades, continuing research has made it more apparent that stuttering is all in the brain.

We are in the middle of an absolute explosion of knowledge being developed about stuttering, Yaruss says.

Theres still a lot to figure out, though. Neuroscientists have observed subtle differences in the brains of people who stutter, but they cant be certain if those differences are the cause or a result of the stutter. Geneticists are identifying variations in certain genes that predispose a person to stutter, but the genes themselves are puzzling: Only recently have their links to brain anatomy become apparent.

Maguire, meanwhile, is pursuing treatments based on dopamine, a chemical messenger in the brain that helps to regulate emotions and movement (precise muscle movements, of course, are needed for intelligible speech). Scientists are just beginning to braid these disparate threads together, even as they forge ahead with early testing for treatments based on their discoveries.

Looking at a standard brain scan of someone who stutters, a radiologist wont notice anything amiss. Its only when experts look closely, with specialized technology that shows the brains in-depth structure and activity during speech, that subtle differences between groups who do and dont stutter become apparent.

The problem isnt confined to one part of the brain. Rather, its all about connections between different parts, says speech-language pathologist and neuroscientist Soo-Eun Chang of the University of Michigan in Ann Arbor. For example, in the brains left hemisphere, people who stutter often appear to have slightly weaker connections between the areas responsible for hearing and for the movements that generate speech. Chang has also observed structural differences in the corpus callosum, the big bundle of nerve fibers that links the left and right hemispheres of the brain.

These findings hint that stuttering might result from slight delays in communication between parts of the brain. Speech, Chang suggests, would be particularly susceptible to such delays because it must be coordinated at lightning speed.

Chang has been trying to understand why about 80 percent of kids who stutter grow up to have normal speech patterns, while the other 20 percent continue to stutter into adulthood. Stuttering typically begins when children first start stringing words together into simple sentences, around age 2. Chang studies children for up to four years, starting as early as possible, looking for changing patterns in brain scans.

Its no easy feat to convince such young children to hold still in a giant, thumping, brain-imaging machine. The team has embellished the scanner with decorations that hide all the scary parts. (It looks like an ocean adventure, Chang says.) In kids who lose their stutter, Changs team has observed that the connections between areas involved in hearing and ones involved in speech movements get stronger over time. Butthat doesnt happen in children who continue to stutter.

In another study, Changs group looked at how the different parts of the brain work simultaneously, or dont, using blood flow as a proxy for activity. They found a link between stuttering and a brain circuit called the default mode network, which has roles in ruminating over ones past or future activities, as well as daydreaming. In children who stutter, the default mode network seems to insert itself like a third person butting in on a romantic date intothe conversation between networks responsible for focusing attention and creating movements. That could also slow speech production, she says.

These changes to brain development or structure might be rooted in a persons genes, but an understanding of this part of the problem has also taken time to mature.

In early 2001, geneticist Dennis Drayna received a surprising email: I am from Cameroon, West Africa. My father was a chief. He had three wives and I have 21 full and half siblings. Almost all of us stutter, Drayna recalls it saying. Do you suppose there could be something genetic in my family?

Drayna, who worked at the National Institute on Deafness and Other Communication Disorders, already had a longstanding interest in the inheritance of stuttering. His uncle and elder brother stuttered, and his twin sons did so as children. But he was reluctant to make a transatlantic journey based on an email, and wary that his clinical skills werent up to analyzing the familys symptoms. He mentioned the email to current National Institutes of Health director Francis Collins (director of the National Human Genome Research Institute at that time), who encouraged him to check it out, so he booked a ticket to Africa. He has also traveled to Pakistan, where intermarriage of cousins can reveal gene variants linked to genetic disorders in their children.

Even with those families, finding the genes was slow going: Stuttering isnt inherited in simple patterns like blood types or freckles are. But eventually, Draynas team identified mutations in four genes GNPTAB,GNPTGandNAGPAfrom the Pakistan studies, andAP4E1from the clan in Cameroonthat he estimates may underlie as many as one in five cases of stuttering.

Oddly, none of the genes that Drayna identified have an obvious connection to speech. Rather, they all are involved in sending cellular materials to the waste-recycling compartment called thelysosome. It took more work before Draynas team linked the genes to brain activity.

They started by engineering mice to have one of the mutations theyd observed in people, in the mouse version ofGNPTAB, to see if it affected the mices vocalizations.Mice can be quite chatty, but much of their conversation takes place in an ultrasonic range that people cant hear. Recording the ultrasonic calls of pups, the team observed patterns similar to human stuttering. They have all these gaps and pauses in their train of vocalizations, says Drayna, who cowrote an overview ofgenetics research on speech and language disordersfor theAnnual Review of Genomics and Human Genetics.

Still, the team struggled to spot any clear defect in the animals brains until one determined researcher found that there were fewer of the cells called astrocytes in the corpus callosum. Astrocytesdo big jobs that are essential for nerve activity: providing the nerves with fuel, for example, and collecting wastes. Perhaps, Drayna muses, the limited astrocyte population slows down communication between the brain hemispheres by a tiny bit, only noticeable in speech.

Draynas research has received mixed reviews. Its really been the pioneering work in the field, says Angela Morgan, a speech-language pathologist at the University of Melbourne and Murdoch Childrens Research Institute in Australia. On the other hand, Maguire has long doubted that mutations in such important genes, used in nearly all cells, could cause defects only in the corpus callosum, and only in speech. He also finds it difficult to compare mouse squeaks to human speech. Thats a bit of a stretch, he says.

Scientists are sure there are more stuttering genes to find. Drayna has retired, but Morgan and collaborators areinitiating a large-scale studyin the hopes of identifying additional genetic contributors in more than 10,000 people.

Maguire has been tackling stuttering from a very different angle: investigating the role of dopamine, a key signaling molecule in the brain. Dopamine can ramp up or down the activity of neurons, depending on the brain location and the nerve receptors it sticks to. There are five different dopamine receptors (named D1, D2, and so on) that pick up the signal and respond.

During the 1990s, Maguire and colleagues were among the first to use a certain kind of brain scan, positron emission tomography, on people who stutter. They foundtoomuch dopamine activityin these peoples brains. That extra dopamine seems to stifle the activity of some of the brain regions that Chang and others have linked to stuttering.

Backing up the dopamine connection, other researchers reported in 2009 that people with a certainversion of the D2 receptor gene, one that indirectly enhances dopamine activity, are more likely to stutter.

So Maguire wondered: Could blocking dopamine be the answer? Conveniently, antipsychotic drugs do just that. Over the years, Maguire has conducted small, successful clinical studies with these medications includingrisperidone,olanzapineandlurasidone. (Personally, he prefers the last because it doesnt cause as much weight gain as the others.) The result: Your stuttering wont completely go away, but we can treat it, he says.

None of those medications are approved for stuttering by the US Food and Drug Administration, and they can cause unpleasant side effects, not just weight gain but also muscle stiffness and impaired movement. In part, thats because they act on the D2 version of the dopamine receptor. Maguires new medication, ecopipam, works on the D1 version, which he expects will diminish some side effects though hell have to watch for others, such as weight loss and depression.

In a small study of 10 volunteers, Maguire, Yaruss and colleagues found that people who took ecopipamstuttered lessthan they did pre-treatment. Quality-of-life scores, related to feelings such as helplessness or acceptance of their stutter, also improved for some participants.

Ecopipam isnt the only treatment under consideration. Back in Michigan, Chang hopes thatstimulation of specific parts of the brain during speech could improve fluency. The team uses electrodes on the scalp to gently stimulate a segment of the hearing area, aiming to strengthen connections between that spot and the one that manages speech movements. (This causes a brief tickle sensation before fading, Chang says.) The researchers stimulate the brain while the person undergoes traditional speech therapy, hoping to enhance the therapys effects. Because of the Covid-19 pandemic, the team had to stop the study with 24 subjects out of a planned 50. Theyre analyzing the data now.

Dopamine, cellular waste disposal, neural connectivity how do they fit together? Chang notes that one of the brains circuits involved in stuttering includes two areas that make and use dopamine, which might help explain why dopamine is important in the disorder.

She hopes that neuroimaging can unite the different ideas. As a first stab, she and collaborators compared the problem areas identified by her brain scans tomaps of where various genes are active in the brain. Two of Draynas genes,GNPTGandNAGPA, were active at high levels in the speech and hearing network in the brains of non-stutterers, she saw. That suggests those genes are really needed in those areas, bolstering Draynas hypothesis that defects in the genes would interfere with speech.

The team also observed something novel: Genes involved in energy processing were active in the speech and hearing areas. Theres a big rise in brain activity during the preschool years, when stuttering tends to start, Chang says. Perhaps, she theorizes, those speech-processing regions dont get all the energy they need at a time when they really need to be cranking at maximum power. With that in mind, she plans to look for mutations in those energy-control genes in children who stutter. There are obviously a lot of dots that need to be connected, she says.

Maguire is also connecting dots: He says hes working on a theory to unite his work with Draynas genetic findings. Meanwhile, after struggling through med school interviews and choosing a career in talk therapy despite his difficulties with speech, hes hopeful about ecopipam: With colleagues, hes starting a new study that willcompare 34 people on ecopipam with 34 on placebo. If that treatment ever becomes part of the standard stuttering tool kit, he will have realized a lifelong dream.

Amber Dance is an award-winningfreelance science journalist based in Southern California. She contributes to publications includingPNAS Front Matter,The Scientist, andNature. Find Amber on Twitter @amberldance

A version of this article was originally published at Knowable Magazine and has been republished here with permission. Knowable can be found on Twitter @KnowableMag. Sign up for their newsletter here.

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'It's all in the brain': The science behind stuttering - Genetic Literacy Project

Gene Therapy Market - Snapshot

Introduction of new production, availability of reimbursement together with high occurrences of cancer are estimated to propel growth of the global gene therapy market in the years to come. Gene therapy refers to an experimental technique, which utilizes genes for the prevention and treatment of various diseases. It is expected that in the near future, this technology could assist doctors to place a gene into the cells of a patient for the purpose of his treatment. This therapy could be used as an alternative to surgery or drugs. Scientists are examining various approaches to this therapy, which could comprise

Gene therapy has emerged as a promising treatment option for a large number of diseases such as certain viral infections, certain cancers, and inherited disorders. This factor is likely to work in favor of the global gene therapy market in the years to come.

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Progress in Gene-editing and Genomics Tools to Stoke Demand of Gene Therapy

CAR T-cell use has recently garnered considerable attention from the sponsors following the exhibition of its immense promise in the treatment of several diseases. The promising future of CAR T-cell is estimated to amplify the growth opportunities of the global gene therapy market. Sponsors hail CAR T-cell use as a brand new business model of the future.

In the pipeline of pharmaceutical industry, gene therapy account for a considerable share and this trend is likely to continue in the years to come. In addition, significant advancement has been made in the fields of cellular and molecular biology is likely to fuel growth of the global gene therapy market in the years to come. rapid technological progress made in the gene-editing and genomics tools are further estimated to drive the demand for gene therapy.

Global Gene Therapy Market Snapshot

Expanding at a stellar, double-digits CAGR (Compound Annual Growth Rate) of 40% over the forecast period of 2018 to 2026, the global gene therapy market is a dizzying trajectory, marking out a rosy landscape for players operating in the playfield. As per a Transparency Market Research report, based on extensive primary and secondary research, states that over the period states, the market would accrue a worth of USD 5164.03 million a steep and impressive increase from the USD 17 million worth noted in 2017.

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Fixing defective genes via introduction of new and healthy ones to fix severe genetic and chronic disorders is seeing an upward curve in demand for reasons of improved medical outcomes, major leaps in terms of technological advancement and minimal die-effects as compared to alternatives. Some of the most significant alternatives include surgery, and drug use.

Some of the most significant factors that the analysts of the report note include focused efforts towards marketing and commercialization, and a slew of approvals of new products hitting the global gene therapy market. Additionally, there are factors such as growing demand experienced for this treatment by a large pool of patients.

It is pertinent to note here that the global gene therapy market is consolidated and is dependent on clinincal research and development of the highest standards in order to chart growth. And, some of the players that operate the market landscape, and are into significant research projects include Gilead Sciences, Inc., Novartis AG, Sibiono GeneTech Co. Ltd., Spark Therapeutics, Inc., CELGENE CORPORATION, and Orchard Therapeutics Limited.

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Yescarta to Dominate Global Gene Therapy Market over the Forecast Period

The global gene therapy market report by TMR is segmented based on type, application, and region. The former includes the only five products that have been approved so far for commercial use. These include Gendicine, Yescarta, Strimvelis, Kymriah, and Luxturna. Riding the first mover benefits, Yescarta helf the dominant position in the market in 2017, and the trend will continue, adding more worth to the sub-segment. This is the product that brought out the initial CAR T therapy in the market for large B-cell lymphoma that relapse.

It is worth noting here that as per the global gene therapy market report, the high incidence of DLBCL and massive commercialization efforts directed towards Yescarta, particularly in Europe, will contribute positively and significantly to the overall growth of the global gene therapy market. The other sub-segment to make a mark over the global gene therapy market landscape will be Luxturna, owing to rising awareness levels and massive efforts towards comercialization.

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Europe to be Ahead of the Global Gene Therapy Market Growth Curve over the Forecast Period

The global gene therapy markets regional segmentation includes incisive growth insights into some of the most significant areas that will shape up the overall growth in the market. These include North America, Europe, and Rest of the World. Researchers involved with the preparation of report claim that a massive chunk of about 40% would be accounted for by Europe over the forecast period. Some of the factors backing-up the market dominance of the region include high incidence of non Hodgkin lymphoma and increase in number of treatment centers into gene therapy.

This growth would be followed by North America region, owing to huge contributions from the United States of America which witnesses about 7500 cases of refractory DLBCL each year. These are ones that qualify for the CAR T therapy.

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Gene Therapy Market Progress in Gene-editing and Genomics Tools to Stoke Demand of Gene Therapy - BioSpace

Two years after acquiring the gene therapy company AveXis, Novartis has renamed it Novartis Gene Therapies to underscore the potential value of developing such treatments for genetic diseases.

This decision was based partly on the success of Zolgensma, originally developed by AveXis, as a gene therapy for spinal muscular atrophy (SMA) that is approved in the U.S., Japan, Europe, and Brazil as an intravenous infusion.

Novartis sees tremendous potential in the future of gene therapy, and weve seen the impact gene therapy can have on so many lives, Vas Narasimhan, CEO of Novartis, in a saidpress release. With the creation of Novartis Gene Therapies, we will continue to advance our gene therapy pipeline for rare genetic diseases, to accelerate the delivery of transformative innovation in areas of high unmet need, and to reimagine medicine for patients all around the world.

Zolgensma targets the underlying cause of SMA, deliveringa working copy of theSMN1gene which is mutated in SMA to motor neurons, the nerve cells that control muscle contraction.

This therapy, the worlds most costly treatment at $2.125 million for one-time use, relies on a genetically engineered virus, called adeno-associated virus (AAV) 9, to transport a workingSMN1 transgene (so-called because its DNA comes from an external source) directly to motor neurons.

In the U.S., the treatment is approved for patients with all SMA types up to the age of 2, given in a single, hourlong intravenous infusion. In Europe, it is approved for those weighing up to 21 kg (about 46 lbs), with a clinicaldiagnosisoftype 1SMA or up to three copies of theSMN2gene.

To date, 600 patients worldwide have been treated with Zolgensma, either through clinical trials, managed access programs, or its commercial availability, Novartis said in its release.

Regularly decisions are expected in Switzerland, Canada, Australia, Argentina, and South Korea this year or in early 2021, it added.

The company has placed a priority on AAV-delivered gene therapies to treat other disorders.The Novartis Gene Therapies research group is reported to be working on treatments for people with Rett syndrome, those with a genetic form of amyotrophic lateral sclerosis (ALS), and withFriedreichs ataxia.

Our patients and their families are the motivation for everything that we do, and under the banner of Novartis Gene Therapies, our dedicated team will continue to create a lifetime of possibilities to people suffering from rare genetic diseases, said David Lennon, president of Novartis Gene Therapies who formerly led AveXis. Becoming Novartis Gene Therapies symbolizes the importance of our gene therapy advances for the future of Novartis and our industry leadership at large.

By unifying the Novartis and AveXis brands, Novartis intends to establish a global presence for Novartis Gene Therapies, Zolgensma, and for potential gene therapies to come.

Total Posts: 85

Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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AveXis Now Known as Novartis Gene Therapies, Focus of Continuing Work - SMA News Today

Technological advancements have blurred the borders of natural biological processes by giving humans more control. One such area is that of gene editing that allows us to modify the childs genetic make up to not only prevent diseases, and lead to a healthier life, but also personality traits for a more fulfilling life. However, this raises question on ethics, consent of the child and rights of parents. RAGHAV AHOOJA,addresses this issue with the lens of state involvement in controlling the private realm.

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WE are at crossroads wherein we may be able to customize and design the futures of our future generations. Lawmakers, thus, need to solve the ethical dilemmas brought about by such giant scientific leaps.

Even though it may sound like science fiction, the future is here.

Gene editing for therapeutic purposes (namely gene therapy) is being conducted for the removal of diseases in humans and foetuses both. When changes are made to the somatic cells, the modifications arent hereditary. However, when the changes are made to the sperm, egg, or embryo, the modifications are transferred on to the next generation. It is done through a process called germline gene editing.

It seems like German philosopher Neitzsches post-human concept of bermensch (translated as beyond-man or superman) might become real. Using a technology known as CRISPR, one can not only treat diseases but also customize a baby in terms of intelligence, athleticism, and so on. This can permanently enhance the lineage of the family.

Believe it or not, the future is here.

Somatic gene editing has been approved in countries like the United States, although with restrictions. It is for the Courts and lawmakers to decide whether this right to enhance children for their own welfare falls within the right to privacy of the parents, or whether the state has a right to curtail such an action.

According to American jurisprudence, there is a private realm of family life which the state cannot enter. Yet time and again the state has entered this realm, claiming a legitimate interest in regulating the family, especially for the welfare of the child. Thus, whilst there exists a right to privacy under the Fourteenth Amendment, it is not absolute.

In the famous case of Roe v. Wade, the United States Supreme Court held that the right to abortion is embedded in the right to privacy of the parent bearing the child. While the judgment was pro-choice, gene editing doesnt quite fit the bifurcated and antagonistic pro-choice v. pro-life debate. It gives parents the choice to genetically edit their children, and the aim of such editing inter alia is to eradicate disease and enhance children for their own welfare.

(Credit: Edward Jenner, Source: Pexels)

Germany, as opposed to the US, recognises the unborn as an individual with a genetically determined identity, which is unique and inseparable. According to German courts, as the unborn baby grows, it does not only develop into a human being but develops as a human being and is worthy of human dignity. Such human dignity would also include the right to live a dignified life, which is free of disease. Therefore, a blanket ban on gene editing would be violative of human dignity.

It is quite clear that therapeutic gene editing is not violative of human dignity, insofar its aim is to eradicate disease. However, such human dignity also includes the right to free development of personality.

It is quite clear that therapeutic gene editing is not violative of human dignity, insofar its aim is to eradicate disease. However, such human dignity also includes the right to free development of personality.

A plain reading of the German constitutional text would suggest that non-therapeutic editing for personality factors is violative of human dignity. But to the contrary, heritable gene editing for purposes such as personality building will be permissible for strengthening the autonomy of the child. Furthermore, it must be for the welfare of the child and must not restrict the free development of their personality. A thumb rule could be whether the child would subsequently consent to such a modification.

Thus, there is a tripartite relationship of the right of the parents to choose the genetic makeup of their children, the right of the state to regulate such an act, and the right of the unborn baby to consent to such editing.

In India, guidelines permitting development of therapeutic gene editing products were introduced. Currently, heritable gene editing can only be done for purposes of experimentation and the embryo cannot have a life beyond 14 days. Thus, heritable gene editing is yet not fully permitted in India. However, there is scope as the Indian Supreme Court in K.S. Puttaswamy (2017) recognised that the right to privacy encompasses family affairs and childrearing. This would possibly entail the parents right to enhance their child as an extension of their right to choose.

It is an established position in law that technology mustnt be prohibited due to a mere possibility of harm. Rather, a positivist approach must be adopted so as to do the greatest good to the greatest number. In fact, a recent report by a German government-appointed council of experts stated that heritable gene editing is not violative of human dignity.

Further, a joint statement by the councils of the United Kingdom, France, and Germany stated that heritable gene editing is permissible. However, there must be a risk assessment and the risk must be brought down to a minimum acceptable level.

And that at the heart of this liberty lies the right to define ones own concept of existence, of meaning, of the universe, and of the mystery of human life, without the interference of the state.

The question, when looked at more deeply, is whether the personality and well-being of future generations ought to be subjected to medical decisions or not.

Thus, there is a tripartite relationship of the right of the parents to choose the genetic makeup of their children, the right of the state to regulate such an act, and the right of the unborn baby to consent to such editing.

The American Supreme Court in Planned Parenthood v. Casey has reiterated that the matters involving the intimate choices of a person are central to dignity and autonomy protected under liberty enshrined in the American Constitution. And that at the heart of this liberty lies the right to define ones own concept of existence, of meaning, of the universe, and of the mystery of human life, without the interference of the state.

(Credit: Ian Panelo, Source: Pexels)

Ultra-modern technologies such as artificial wombs make one think whether a birth is really an event, or a process, and if so then where does the process begin?

Partial ectogenesis (the growth of a baby outside the womb) is already happening. But in time, we might be able to carry out full ectogenesis. As the reliability of such technologies increases, so does their capability. The potential to live outside the mothers womb as opposed to the usual 24 weeks would begin right from the stage of development of the foetus, which is at 8 weeks. Further, with the help of biotech, the ability of an unborn baby to live outside the mothers womb might begin right at fertilisation.

Do we fast forward using techno solutionism or do we let evolution do its thing?

The American Courts have held that an individual whether single or married has the right to privacy which the state cannot infringe. Thus, even a single parent, out of wedlock, can bear such a child and the right to genetically edit unborn babies would be extended to them. The mother and father would be on an equal footing while deciding whether to genetically edit the baby or not.

The aim of the process of childrearing is to produce children with favourable traits and personality and allow them to have a dignified life.

In the first such successfully germline edited babies, scientists predict that it might have actually led to having enhanced their ability to learn and form memories. In another case of successful gene therapy, young children were saved from potentially deadly diseases and lives of isolation.

Therefore, the moot question is: Do we fast forward using techno solutionism or do we let evolution do its thing? Where do we draw the line? Should one circumscribe the limits of technology, or let it take a well-designed course?

Believe it or not, the future is here.

Where does that leave us?

It is for us to decide.

(Raghav Ahooja is a final year student at Rajiv Gandhi National Law University, Punjab. Views are personal.)

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Gene Editing: Do We Have The Right to Genetically Enhance Our Children? - The Leaflet

NEW YORK & AMSTERDAM--(BUSINESS WIRE)--Neogene Therapeutics, Inc., a pre-clinical stage biotechnology company pioneering a new class of fully personalized neo-antigen T cell therapies to treat cancer, today announced that it has raised $110 million in a Series A financing. The financing was co-led by EcoR1 Capital, Jeito Capital and Syncona, with participation from Polaris Partners and Pontifax. Seed investors Vida Ventures, TPG and Two River also participated in the round.

Neogene, a Two River company, was founded in 2018 by a team of world-class cell therapy experts to advance the development of neo-antigen T cell therapies. Carsten Linnemann, Ph.D., Chief Executive Officer of Neogene, and Ton Schumacher, Ph.D., Principal Investigator at the Netherlands Cancer Institute, Oncode Institute and 2020 recipient of the Dutch Research Councils Stevin Award co-founded the Company with individual investments by cell therapy industry veterans Arie Belldegrun, M.D. FACS, founder of Kite Pharma, Inc. and Co-Founder and Executive Chairman of Allogene Therapeutics, Inc. and David Chang, M.D., Ph.D., Co-Founder, President and Chief Executive Officer of Allogene. Dr. Linnemann and Dr. Schumacher previously co-founded T-Cell Factory B.V., a company acquired by Kite Pharma in 2015.

Dr. Schumacher, an internationally leading immunologist in the areas of neo-antigen biology and T cell engineering, developed the seminal concepts of Neogenes proprietary technology. Neogenes platform allows for the isolation of neo-antigen specific TCR genes from tumor biopsies that are routinely obtained from cancer patients during treatment. The tumor-infiltrating lymphocytes (TIL) obtained by these tumor biopsies frequently express TCRs specific for mutated proteins found in cancer cells (neo-antigens). The Companys proprietary technology uses state-of-the-art DNA sequencing, DNA synthesis and genetic screening tools to identify such neo-antigen specific T cell receptor genes within tumor biopsies with high sensitivity, specificity and at scale. The isolated TCR genes are subsequently engineered into T cells of cancer patients to provide large numbers of potent T cells for therapy.

Neogene is committed to forging a path for new fully personalized engineered T cell therapies in solid cancer that are redirected towards neo-antigens found on cancer cells, said Dr. Linnemann. While engineered T cell therapies have transformed the treatment paradigm for patients with hematologic malignancies, the industry has struggled to translate this success to the enormous unmet need in patients with advanced solid tumors. We believe that through a fully individualized approach using patient-specific TCRs to target neo-antigens, engineered T cell therapy can become broadly accessible to these patients. We are excited that our vision is shared by an outstanding syndicate of marquee investors, who have a deep understanding of and commitment towards the development of novel cell therapies in oncology.

Neo-antigens represent ideal targets for cancer therapy, as they inevitably arise from DNA mutations that enable tumor development in the first place. Further supporting this concept is clear, correlative evidence linking T cell reactivity against neo-antigens with tumor regression in several patients, said Dr. Schumacher. The Neogene platform makes it possible to exploit the neo-antigen reactive TCRs that are present in TIL without a requirement for viable tumor material. In addition, its syn-bio based approach offers major advantages with respect to standardization and scalability and will be critical to achieve our goal of bringing personalized engineered T cell therapies to patients.

In this Series A financing, Neogene expands its distinguished investor base with leading health-care investors from both the U.S. and Europe. For the seed-investors Vida Ventures, TPG and Two River, Neogene marks the second major collaboration in the cell therapy space after the launch of Allogene Therapeutics in 2018. Neogenes seed-financing in 2019 enabled the Company to achieve proof-of-concept for its neo-antigen technology platform and built on the respective expertise of Vida Ventures, Two River and TPG in the gene and cell therapy space.

We believe that Neogenes technology and therapeutic approach has the potential to become a game changer for the treatment of cancer, said Oleg Nodelman, Founder and Managing Director of EcoR1 Capital. We are impressed by the bold vision of the management team and are thrilled to support Neogene as it advances its mission of developing novel therapies for cancer patients in need.

Neogenes approach perfectly aligns with Jeitos mission. Jeito was launched recently to support new and established entrepreneurs aspiring to help patients in need by pioneering novel, ground-breaking medicines underlined by highest quality innovation, said Rafale Tordjman, Founder and Chief Executive Officer at Jeito Capital. We are delighted to welcome Neogene as the first investment into our new portfolio.

We are excited to partner with the outstanding Neogene team, said Martin Murphy, Chief Executive Officer of Syncona. Neogenes technology offers a radically innovative approach to utilize the therapeutic potential of TIL cells by employing state-of-the-art TCR engineering and synthetic biology technologies. Facilitated by the Series A, Neogene intends to further develop its technology with growing offices in Amsterdam and the U.S. with the goal to initiate Phase I clinical studies in 2022.

About Neogene Therapeutics

Neogene Therapeutics, Inc. is a pre-clinical stage biotechnology company pioneering development of next-generation, fully personalized engineered T cells therapies for a broad spectrum of cancers. The Companys engineered T cells target mutated proteins found in cancer cells due to cancer-associated DNA mutations, or neo-antigens, that render tumor cells vulnerable to detection by T cells. Neogenes proprietary technology platform aims to identify TCR genes with specificity for neo-antigens from tumor biopsies. Neogenes novel approach intends to deliver a tailored set of TCR genes for each individual patient, which will be engineered into patient-derived T cells directing them towards neo-antigens in tumor cells, with the goal of providing a fully personalized engineered T cell therapy for cancer.

For more information, please visit http://www.neogene.com, and follow Neogene Therapeutics on LinkedIn.

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Neogene Therapeutics Raises $110 Million Series A Financing to Develop Next-Generation Fully Personalized Neo-Antigen T Cell Receptor (TCR) Therapies...

DetailsCategory: Small MoleculesPublished on Sunday, 20 September 2020 11:08Hits: 263

Five-year data from the SOLO-1 Phase III trial is the longest follow-up analysis for any PARP inhibitor in the 1st-line maintenance setting

WILMINGTON, DE, USA I September 18, 2020 I AstraZeneca and Merck & Co., Inc., (Merck: known as MSD outside the US and Canada) today announced that LYNPARZA demonstrated a long-term progression-free survival (PFS) benefit versus placebo as a 1st-line maintenance treatment in patients with newly diagnosed, advanced BRCA-mutated (BRCAm) ovarian cancer who had a complete or partial response following platinum-based chemotherapy.

Ovarian cancer ranks fifth in cancer deaths among women in the U.S., and in 2020, an estimated 21,750 women in the U.S. will receive a new diagnosis and about 13,940 women will die from ovarian cancer.1

Five-year follow-up data from the Phase III SOLO-1 trial showed LYNPARZA reduced the risk of disease progression or death by 67% (based on a hazard ratio [HR] of 0.33; 95% confidence interval [CI] 0.25-0.43) and improved PFS to a median of 56.0 months versus 13.8 months for placebo. At five years, 48.3% of patients treated with LYNPARZA remained free from disease progression versus 20.5% on placebo. The median duration of treatment with LYNPARZA was 24.6 months versus 13.9 months with placebo.

Susana Banerjee, one of the investigators from the SOLO-1 trial and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Reader at the Institute of Cancer Research, London, said: For patients with newly diagnosed BRCA-mutated advanced ovarian cancer, the benefit derived from two years of maintenance treatment with LYNPARZA continued long after treatment ended. After five years, almost half of these women were free of cancer progression. These results represent a significant step forward in the treatment of BRCA-mutated ovarian cancer.

Jos Baselga, Executive Vice President, Oncology R&D, said: Once a patients ovarian cancer recurs, it has historically been incurable. Even at an advanced stage, we have shown that maintenance treatment with LYNPARZA can help patients achieve sustained remission. Todays results further underline the critical importance of identifying a patients biomarker status at the time of diagnosis to be able to offer a treatment that may help delay disease progression.

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck, said: This is the first trial of a PARP inhibitor to read out a five year follow up and showed LYNPARZA improved progression-free survival to over four and a half years versus 13.8 months with placebo following response to 1st-line platinum-based chemotherapy. This latest data represents a major and significant milestone in a disease which has historically had such a poor prognosis.

Summary of results

LYNPARZA

N=260

Placebo

N=131

LYNPARZA

N=189

Placebo

N=101

0.33 (0.250.43)

The safety profile of LYNPARZA was consistent with previous observations. The most common adverse events (AEs) 20% were nausea (77%), fatigue/asthenia (63%), vomiting (40%), anemia (39%) and diarrhea (34%). The most common grade 3 AEs were anemia (22%) and neutropenia (9%). Twelve percent of patients on LYNPARZA discontinued treatment due to an AE.

The results were presented on Friday, September 18, during the 2020 European Society of Medical Oncology (ESMO) virtual congress.

The Phase III SOLO-1 trial met the primary endpoint of PFS in June 2018, which formed the basis of approvals in the US, the EU, Japan, China, and several other countries.2

INDICATIONS

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

First-Line Maintenance BRCAm Advanced Ovarian Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

First-Line Maintenance HRD Positive Advanced Ovarian Cancer in Combination with Bevacizumab

In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:

Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Maintenance Recurrent Ovarian Cancer

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

Advanced gBRCAm Ovarian Cancer

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

gBRCAm, HER2-Negative Metastatic Breast Cancer

For the treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer

For the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please click here for complete Prescribing Information, including Patient Information (Medication Guide).

About Ovarian Cancer

Approximately 21,750 women in the United States will be diagnosed with ovarian cancer (including ovarian, fallopian tube and primary peritoneal cancers) in 2020. Among women in the United States, it is the fifth leading cause of cancer death.1

The risk of developing ovarian cancer is increased in women with specific inherited genetic abnormalities, including BRCA mutations.3

About SOLO-1

SOLO-1 was a Phase III randomized, double-blinded, placebo-controlled, multi-center trial to evaluate the efficacy and safety of LYNPARZA tablets (300 mg twice daily) as a maintenance monotherapy compared with placebo in patients with newly diagnosed BRCAm advanced ovarian cancer following first-line platinum-based chemotherapy. The trial randomized 391 patients with a deleterious or suspected deleterious germline or somatic BRCA1 or BRCA2 mutation who were in clinical complete or partial response following platinum-based chemotherapy.

Patients were randomized (2:1) to receive LYNPARZA or placebo for up to two years or until disease progression. Patients who had a partial response at two years were permitted to stay on therapy at the investigators discretion.4 The primary endpoint was PFS and key secondary endpoints included time to second disease progression or death, time to first subsequent treatment and overall survival.2

About LYNPARZA

LYNPARZA (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumors harboring a deficiency in homologous recombination repair, such as mutations in BRCA1 and/or BRCA2.4,5,6 Inhibition of PARP with LYNPARZA leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death.7 LYNPARZA is being tested in a range of PARP-dependent tumor types with defects and dependencies in the DDR pathway.

LYNPARZA is currently approved in a number of countries, including those in the US, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in the US as a 1st-line maintenance treatment with bevacizumab for patients with homologous recombination deficiency (HRD)-positive advanced ovarian cancer. LYNPARZA is approved in the US, Japan, and a number of other countries for the treatment of germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. It is also approved in the US and several other countries for the treatment of germline BRCA-mutated metastatic pancreatic cancer. LYNPARZA is approved in the US for HRR gene-mutated metastatic castration-resistant prostate cancer. Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers.

LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has been used to treat over 30,000 patients worldwide. LYNPARZA has the broadest and most advanced clinical trial development program of any PARP inhibitor, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types. LYNPARZA is the foundation of AstraZenecas industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

About the AstraZeneca and Merck Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize LYNPARZA, the worlds first PARP inhibitor, and KOSELUGO (selumetinib), a MEK inhibitor, for multiple cancer types. Working together, the companies will develop LYNPARZA and other compounds in combination with other potential new medicines and as monotherapies. Independently, the companies will develop LYNPARZA and KOSELUGO in combination with their respective PD-L1 and PD-1 medicines.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients lives and the Companys future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of four scientific platforms Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory & Immunology. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit http://www.astrazeneca-us.com and follow the Company on Twitter @AstraZenecaUS.

REFERENCES

SOURCE: AstraZeneca

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LYNPARZA (olaparib) Improved Median Time Patients Lived Without Disease Progression to Over Four and Half Years in BRCA-mutated Advanced Ovarian...