Category Archives: Gene Medicine

The first time geneticist George Church visited Siberia was the first summer the permafrost melted.

Permafrost by its nature is supposed to stay frozen year-round, but in a marker of encroaching climate change, in 2018 the top layer of soil thawed and didnt refreeze. Microbes began to eat the carbon that had been locked away in the ice and released it into the air as methane gas. Church watched a teammate light a match and ignite a pocket of the gas that hovered over the softening bog they stood in.

That was an ominous sign, Church recalled. Today, he says, thawing permafrost is burping up methane at an alarming rate, given that the gas is 30 times more potent than carbon dioxide in contributing to global warming.

The sight reinforced Churchs determination to combat climate change by ensuring that the worlds permafrost stays frozen, keeping its estimated 1.4 trillion tons of stored carbontwo and a half times more than the Amazon rainforest harborstucked safely away.

His plan for doing so: Genetically modifying a group of elephants to thrive in the cold and moving them north so their daily activities contribute to preserving and restoring Arctic environments.

Harvard Medicine News spoke with Church about this unusual approach to climate mitigation and the latest developments in his labs efforts. Church is the Robert Winthrop Professor of Genetics in the Blavatnik Institute at Harvard Medical School and a founding core member of the Wyss Institute for Biologically Inspired Engineering at Harvard University.

Church: People tend to use the shorthand that were de-extincting mammoths: bringing them back to life after the last of them died about 4,000 years ago. Were not. At least, not in the near future. Were trying to de-extinct genes. The field has actually already done this with two genes that confer cold-resistant properties to organisms. The idea is to safely introduce these and other genes into present-day elephants so the elephants can comfortably live in and restore Arctic environments.

Church: The main reasons have to do with biodiversity and climate mitigation.

A question we get asked frequently is, Why de-extinct something that already had its chance; why dont you focus on endangered species and saving them from going extinct? Well, thats exactly what were doing. Were dealing not with mammoths but with modern endangered species.

All elephant species are endangered. Were trying to give them new land in the Arctic thats far away from humans, who are the major culprits causing extinction. Were trying to cure Asian elephant-specific herpesvirus, which can be deadly, especially in young elephants. Were trying to develop tools that might be useful for other endangered species that other teams might be interested in working on.

The two-for-one is that not only would the elephants get a new homeland, but their homeland is in desperate need of environmental restoration, and they can help. Moving genetically adapted elephants to the Arctic offers an opportunity to sequester, or remove from the atmosphere, significant amounts of carbon and to prevent more carbon from escaping.

Understanding how this might work requires connecting a few dots. Elephants knock over trees, reducing bark that absorbs sunlight and heats the ground. Clearing a portion of the tree cover allows the animals to walk through new areas and pack down the snow there, facilitating permafrost freeze. Otherwise, the snow forms a fluffy, insulating layer that keeps the topsoil warm.

Basically, the idea is that we need to convert a portion of trees in the Arctic back to grass, and elephants are the only living large herbivore that will do that. They do so quickly and easily, and they like doing it. So a genetically adapted elephant-mammoth hybrid might prove to be a good proxy species for the ecological role the woolly mammoth used to play.

Church: Were trying to gather genetic diversity. We know diversity is useful for survival in a changing or new environment, and were getting better at identifying and gathering genes that are important for a given traitin this case, cold tolerance and virus resistance.

Were no longer limited to searching for beneficial genes in one elephant herd or even the global elephant population; now we can go all around the world, even to distant species, and back in time up to 1 million years to discover and obtain those genes. The DNA that mammoths left behind in their bones can offer us the genetic code for traits like warm, woolly hair and thick, subcutaneous fat.

Church: Most of the projects Ive worked on in my careerlike the publicizing and privacy of personal genomes, development of devices that print synthetic DNA, gene drives that eliminate malaria parasites from mosquitoesrequire broad public engagement. The problem isnt always getting scientists engaged; its getting the public engaged. People are focused on how to put food on the table and get their kids educated. The latest cutting-edge scientific thing is not always perceived as important.

As a start, my research group has worked with HMS geneticist Ting Wus Personal Genetics Education Project to brief Congressional staffers, who then bring information back to their constituents. Were working with writers who reach millions of people through their narrativesand the Arctic elephant story resonates particularly well. Were reaching out to representatives of key populations, including people from Indigenous groups, Arctic farming communities, other industries, and governments. Well engage with anyone who wants to participate, whether they take a positive or negative view of the work.

Church: I am a scientific co-founder of Colossal but have no management role there. The company is providing funding for my labs work toward creating an elephant-mammoth hybrid through a sponsored research agreement with Harvard. Its fairly open-ended research that we would have done anyway if wed had the money for itin fact, we were already doing some of the work through sparsely funded or volunteer labor. Now that Colossal has dedicated some funding to it, this work in my lab is a much more concerted and defined project that well be pursuing over the next few years.

Church: Definitely. First of all, climate change itself is a human health issue. Preventing further warming or reversing existing damage by sequestering carbon would safeguard human lives along with the ecosystems.

Side products of the Colossal effort will be technologies from my lab, with an additional potential for great impact on human health. Some of what were doing with reproductive medicine in elephants, like making gametes and finding ways to handle premature births, may open a path into various assistive reproductive technologies in humans, making those procedures safer for all sorts of cases.

There is a lot that human medicine and animal medicine can learn from one another. Weve seen in the past that a lot of our work on reading and writing DNA and developing medical diagnostics and therapeutics is directly translatable to veterinary efforts.

Church: Our lab does a lot of basic engineering and a little bit of basic science, and were heavily dependent on basic science from our close colleagues. An example of such pure science was the discovery of a repetitive family of gene sequences now called CRISPR. That was seen as just a bunch of junk DNA at first, and now it has revolutionized our ability to edit genes for medical and industrial purposes. The genomic sequencing of lots of vertebrate species, including extinct species, was basic science without necessarily any particular goal in mind, and that has been very valuable.

Church: Were trying to efficiently identify and test genes that would provide adaptation to Arctic environments. Weve been developing methods for multiplexed editingthe ability to make thousands of genetic and epigenetic changes at once. This allows us to turn adult elephant cells into pluripotent stem cells, introduce the changes, and mature the cells back into adult-like tissues fast, within four days to a couple of weeks, so we can then study our genes of interest as a batch. Speed and volume are important because introducing a single change and waiting for an entire elephant embryo to mature would take 22 months. In the time it would take to study every gene candidate that way, the climate crisis would either be resolved by some other method or have caused societal collapse.

Our record for multiplexed editing in general now is 22,000 edits in a few days. The number of edits well need to make in the elephant isnt clear yet. It could be as few as 40, which is the number of changes we made in the pig genome to facilitate organ transplantation to humans, and it probably wont be more than 500,000, which is the number of fixed genetic differences between mammoths and elephants.

Were also pushing the science forward on reprogramming techniques to grow healthy gametes and promote safe in vitro fertilization and embryonic development so that when the research is ready to deploy, elephants can successfully gestate the genetically modified offspring. Because we dont want to hinder the reproduction of endangered species.

Church: The big ones are the multiplexed editing and both accelerated and normal in vitro development. For initial testing, you want accelerated development. For complete testing and to ultimately birth calves, you need normal-speed development.

Getting ready for further down the road: Strategies are being developed for where the elephants should be located, how to guide them away from places where people live and toward places where they could contribute to reducing carbon risk, and what the appropriate landscapes and flora should be, including specific flowering plants they like to eat. These behavioral and geopolitical realities might take more time than the actual engineering.

People with sophisticated modeling tools want to be involved. Its better to find out now with a good model whether theres a problem than six years from now. Carbon reserves vary from place to place in the Arctic, and it might take dispersing elephants over only a small fraction of its 20 million square kilometers, in precisely targeted areas, to get the climate impact we want.

Church: The six-year estimate for birthing an Arctic-adapted elephant calf is an ideal-case scenario based on working backwards from the 22-month gestation period, figuring another two years to achieve successful IVF embryos in mice, and two years in between for debugging the system for producing healthy elephant fetal development. That assumes everything goes smoothly along the way, which doesnt typically happen.

I used to predict that reaching the final stage would take a very long time, maybe decades, because we didnt have any appreciable funding, and it does depend on funding. Today, I think six years is a good goal to strive forbut its not a promise. Its a similar kind of ambitious, engineering-focused, team-based target that President Kennedy set when he declared we would put a person on the moon within a decade. The scientific challenges of this project are considerable but ultimately surmountable. The bioethical dimensions are paramount. The execution will no doubt be daunting. However, we owe it to science, to humankind, to our fellow species, and to our planet to try.

This interview was edited for length and clarity.

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A mammoth solution - Harvard Office of Technology Development

PARIS, Nov. 15, 2021 /PRNewswire/ --Coave Therapeutics ('Coave'), a clinical-stage biotechnology company focused on developing life-changing gene therapies in rare Ocular and CNS (Central Nervous System) diseases, today announced that it has strengthened its leadership team with the appointments of Thomas Blaettler MD, as Chief Medical Officer, and Patricia Franon PhD, to the newly created position of Chief Operating Officer.

"I am very pleased to welcome Thomas and Patricia to the leadership team at Coave. Their collective accomplishments and deep domain expertisein neuroscience, cell and gene therapy, in addition to their extensive clinical drug development and project management experience will be invaluable as we progress our lead candidate through clinical development and advance our pipeline of novel gene therapies into clinical development targeting rare Ocular and CNS diseases," said Rodolphe Clerval, CEO.

Thomas Blaettler, MD

Dr Blaettler is an expert in the neuroscience therapy area, having over 25 years' experience in the field, both in clinical residency and industry. Thomas joins Coave from Orphazyme A/Swhere, since 2016, he served as Chief Medical Officer and was responsible for devising the clinical development strategy and progressing the company's rare neurodegenerative pipeline. In addition to championing the clinical and regulatory strategy, Thomas has contributed to Orphazyme's IPO on both the Copenhagen and Nasdaq stock exchanges. Prior to Orphazyme, Thomas held global leadership roles within the clinical neuroscience divisions at both Roche and Bristol Myers Squibb, with a further neuroscience translational medicine role at Novartis.

"I am delighted to be joining Coave at such an exciting stage of development," said Dr Blaettler. "I look forward to progressing CTx-PDE6b through the clinic, and to contributing to the advancement of the company's pipeline of next-generation gene therapies, which have the potential to deliver life changing outcomes for rare disease patients."

Thomas completed his Doctor of Medicine at the University of Zurich in 1994 and went on to complete almost 10 years of clinical residency and research in the neurology field. Thomas gained board certification from the Swiss Society of Neurology in 2003.

Patricia Franon PhD

Dr Franon is an experienced biotech professional with over 20 years' experience leading global CMC and regulatory strategies for the accelerated development of innovative biologics, advanced cell & gene therapies. Patricia joins Coave from Skinosive where she served as Chief Operating/Technology Officer, managing operational aspects of the business, proactively driving the company towards achieving its development goals. Patricia has also held various clinical development roles at Sartorius, Neuro-Sys, Enterome, Evry, Cellectis, Anaconda Pharma and Sanofi, managing all aspects of product development, coordinating multiple studies, selecting partners and managing regulatory processes.

"Coave's ALIGATER technology is truly innovative and demonstrates an important ability to provide gene therapies with increased tissue targeting and transduction, designed to enhance their potency and efficacy," added Dr Franon. "I look forward to working with Rodolphe and the team to drive the company forward on its mission of improving the effectiveness of advanced gene therapies for rare diseases."

Patricia obtained her PhD in Molecular and Cellular Biology from Paris VI University and completed postdoctoral research at McGill University.

About Coave Therapeutics

Coave Therapeutics is a clinical-stage biotechnology company focused on developing life-changing gene therapies in rare ocular and CNS (Central Nervous System) diseases.

Coave Therapeutics' next-generation AAV-Ligand Conjugate ('ALIGATER') platform enables targeted delivery and enhanced gene transduction to improve the effectiveness of advanced gene therapies for rare diseases.

The Company is advancing a pipeline of novel therapies targeting rare ocular and brain diseases where targeted gene therapy using AAV-Ligand has the potential to be most effective.

Coave Therapeutics, which is headquartered in Paris (France), is backed by leading international life science and strategic investors Seroba Life Sciences, Tha Open Innovation, eureKARE, Fund+, Omnes Capital, V-Bio Ventures, Kurma Partners, Idinvest, GO Capital, Sham Innovation Sant/Turenne.

For more information, please visit http://www.coavetx.com or follow us on LinkedIn http://www.linkedin.com/company/coavetx/

CONTACTS

Coave Therapeutics Rodolphe Clerval, CEO [emailprotected]

MEDiSTRAVA ConsultingSylvie Berrebi, Eleanor Perkin, Mark Swallow PhD[emailprotected] Tel: +44 (0)7714 306525

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Coave Therapeutics Strengthens Leadership Team with the Appointments of Thomas Blaettler MD as Chief Medical Officer and Patricia Franon PhD as Chief...

The two partners will work together to identify areas ripe for innovation, hire a Founding Analyst to evaluate potential approaches for scientific and commercial viability, build teams around the optimal approaches, and create one or more high-impact ventures.

As well as improving patient outcomes, the partnership hopes to spur innovation in the sector and open up job opportunities.

The CGT Catapult was established as an independent center of excellence to advance the UK cell and gene therapy industry, bridging the gap between scientific research and full-scale commercialization. Deep Science Ventures, meanwhile, uses a unique venture creation process to create, spin-out and invest into science companies: earmarking high-impact ventures across pharmaceuticals, energy, agriculture and computation.

Recent advances in cell and gene therapies promise potential cures to some of mankind's most devastating diseases, the partners said as they announced their collaboration.

However, major hurdles still need to be overcome, including ensuring target specificity and effective manufacturing at scale.

This collaboration will leverage Deep Science Ventures novel outcome-focused approach to venture creation, which combines available scientific knowledge and founder-type scientists into high-impact ventures. CGT Catapult will provide its cell and gene therapy-specific technical, non-clinical and regulatory expertise to apply Deep Science Ventures approach to the ATMP sector.

Deep Science Ventures has so far built and invested in nine brand new companies in the curative therapeutics space, including three oncology ventures last year with Cancer Research UK. The nine companies are ConcR, ImmTune, Enedra, Neobe and Stratosvir (oncology); Reflection Therapeutics (neurodegeneration) and CC Bio and Ancilia (microbiome and AMR).

Only 10% of drugs succeed at Phase 3 clinical trials. DSV says the current rate of therapeutic failure is unsustainable and unnecessary: with various reasons ranging from poor models to lack of specificity.

It says the emergency of personalized and precision therapeutics creates the opportunity to address entrenched and repeated failures across the process of bringing a new product to market.

This includes leveraging computation to unpick complex dynamic systems, move the computation into the therapeutic itself, address root causes directly and drive the creation of better models and markers.

At DSV we aim to get back to first principles and understand the root cause and bottlenecks that have led to past failures. Not just failures in the science but perhaps even more importantly, to discover the gaps and biases in the innovation pipeline.

Our approach is to forge a less linear R&D process identifying analytical and model approaches that fully capture complexity and patient specificity; and force a truly multi-stakeholder creation process with academics, venture capital, charities and industry engaged in the design process from day one.

CGT Catapult will be speaking in our upcoming webinar: 'Cell and gene therapies: How can their promise be realized?'. Register for free here.

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Cell and Gene Therapy Catapult and Deep Science Ventures collaborate to overcome barriers in ATMPs - BioPharma-Reporter.com

Dr Pengyi Yang uses computational expertise to build virtual cells.

DrPengyiYanghasreceived one of two annual $55,000 Metcalf Prizes from the National Stem Cell Foundation of Australia inrecognition of his leadership in the field.

DrYangholds a joint position with the University of SydneySchool of Mathematics & Statistics, theCharles Perkins Centreand theChildren's MedicalResearch Institute. His work aims toremove much of the guesswork from stemcell science and eventually stemcell medicine.

Todays stem cell treatmentshave beenthe product of trial anderror, DrYang said.

My virtual stem cell will allow us to understand whats happening inside a single stem cell that makes it decide what type of cell it will becomesuch as, but not limited to,hair, skin, muscle, nerveorbloodcells.

He is mapping the many, complex influencescontrollingstem cells andthe waythey specialise into different cell types.

Stem cells are amazing because they can produce any kind of cell in the body. Theyre fundamental toregenerative medicine,DrYang said.

But, when theircontrols fail,rogue stem cells can lead to cancer.

Allhumanlifestartsas a single stem cell. It goes on to produce cells that eventually become every type of tissue and organ of the human body. Even in adulthood, stem cellsrepairandreplacetissue all the time.

People are excited about the potential of stem cell medicine, but thereality is extremely complicated. Thousands of genes, complex gene networks, environmental factors, and an individuals own health are all involved in pushing stem cells to become specific cell types,DrYang said.

DrYang, a computerscientist turned stem cell researcher, uses computational science and statistics to understand how stem cells function at a fundamental level work that will be useful forthe entire stem cell field ofresearch.

We need a computermodel to bring all of these influences togetherso we can identify the specific gene networks that drive the stem cells towards each cell type,he said.

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Dr Pengyi Yang wins National Stem Cell Foundation Metcalf Prize - News - The University of Sydney

SEATTLE, Nov. 12, 2021 /PRNewswire/ --The global regenerative medicine market is estimated to account for25,959.5Mn in terms of value by the end of 2028.

The field of regenerative medicine encompasses three areas that researchers from all around the world have been investigating: stem cell therapies, adult stem cell therapies, and gene therapy.Regenerative medicine seeks to treat illness by using the body's own ability to make new tissue, organ, or even cells. This field is the subject of regenerative medicine research all over the world. While the field of regenerative medicine continues to grow, there has been a lot of interest from the pharmaceutical and biotech industries with the hopes of finding treatments for age-related illnesses such as Alzheimer's and Parkinson's disease. However, the field of stem cell therapies is relatively new with researchers discovering and testing ways of producing new stem cells from adult cells in the human body. These stem cells are then injected into the patient in hopes that the new cells will grow and multiply and thus cure the patient of an illness or disease. Stem cell therapies has been successful in many cases, but scientists continue to research and test more effective methods. Another area that regenerative medicine looks into is the development of new and effective organs for transplant. Scientists and doctors have been trying for years to develop organs that can replace ones that are damaged or destroyed in certain accidents or diseases.

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Market Drivers:

Growing initiatives by key players to launch various regenerative medicine therapies is driving growth of the regenerative medicine market. For instance, in May 2021, The SingHealth Duke-NUS Academic Medical Centre (AMC) has announced the launch of a research institute and disease center that will advance regenerative medicine and introduce cellular therapies to improve patient care.

The increasing focus of key players on R &D of gene and stem cell therapy is again fostering growth of the market. For instance, in October 2021, VectorBuilder Inc. and Landau Biotechnology Co., have entered into a strategic partnership to establish the first primate gene therapy R&D center. The center will build advanced vector screening and optimization platforms to provide unique CRO services to the rapidly growing gene and cell therapy industry.

Market Opportunities:

Growing incidence of bone and joint disorders and orthopedic surgeries around the globe is expected to offer lucrative growth opportunities to the regenerative medicine market. According to Joint-surgeon.com, more than 24,000 orthopedic patients are treated per year. More than 2400 surgical procedures are performed per year. More than 250 international patients are treated per year.

Increasing development and launch of various novel innovative regenerative medicines products is expected to serve potential growth opportunities. For instance, in January 2021, Essent Biologics, a nonprofit biotechnology company, announced its launch to provide human-derived biomaterials and 3D biology data to the regenerative medicine research community.

Market Trends:

Growing number of public-private partnerships and agreements among key players is a major trend observed in the market. For instance, in February 2018, The National Institute of Standards and Technology (NIST) and the Standards Coordinating Body for Gene, Cell and Regenerative Medicines and Cell-based Drug Discovery (SCB) have partnered for the development of standards for accelerating R&D and clinical translation of regenerative medicine and advanced therapies.

The increasing focus of key players to invest in the field of regenerative medicine is expected to stimulate growth of the market. For instance, in September 2021, PTC Therapeutics announced that it will provide initial funding of $60 million to the Spinal Muscular Atrophy (SMA) Foundation to discover and develop regenerative medicines for neuromuscular diseases to help restore patients lost function.

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Competitive Landscape:

Major players engaged in the global regenerative medicine (Bone and Joint) market include Anika Therapeutics, Inc, Baxter International, Inc., Arthrex, Inc., CONMED Corporation, Medtronic, Plc, Smith & Nephew plc, Johnson & Johnson, Stryker Corporation, Aziyo Biologics, Zimmer Holdings, Inc., and Ortho Regenerative Technologies Inc etc.

Market segmentation:

Global Regenerative Medicine (Bone and Joint) Market, By Technology:

Global Regenerative Medicine (Bone and Joint) Market, By Application:

By Geography:

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Regenerative Medicine Market to reach US$ 25,959.5 Mn by end of 2028, Says Coherent Market Insights - PRNewswire

Identifying the genetic causes of rare neurodevelopmental disorders can be quite challenging. In a recent study, a global scientific team including researchers from Baylor College of Medicine, worked to find genetic answers for Turkish families.

Its very common in clinical practice to see a patient whose characteristics do not match what has been documented in the literature, limiting the physicians ability to guide clinical care and provide information about which other family members might be at risk, said Dr. Tadahiro Mitani, a postdoctoral associate in Dr. James R. Lupskis lab at Baylor College of Medicine.

In the current study, explains Mitani, who is the first author of the work by a team of 50 investigators from around the world, the researchers looked to identify the genetic causes of rare neurodevelopmental disorders in 234 subjects and 20 previously unsolved cases of affected families of the Turkish population.

To achieve this goal, we integrated improved genome-wide screening technologies, including exome sequencing and whole-genome sequencing, and newly developed computational tools and bioinformatic analyses to improve our ability to identify the genetic underpinnings of rare neurodevelopmental conditions, said co-corresponding author Dr. Davut Pehlivan, assistant professor of pediatrics neurology at BCM.

The researchers started this project in 2011 and over the years developed close collaborations with physicians and patients worldwide, as well as with researchers in the fields of genetics, genomics and bioinformatics. The team used GeneMatcher, a freely accessible web-based matchmaking service designed to enable connections between clinicians and researchers from around the world who share an interest in the same gene or genes.

The team identified new genes and confirmed genes previously associated with neurodevelopmental disorders.

They were able to make a molecular diagnosis in 181 of 254 (71%) of the individuals in this study and in approximately 80% of neurodevelopmental disorders overall. Twenty of the 181 diagnosed individuals had been studied before, but at the time the researchers did not identify a genetic diagnosis.

Our findings confirm that applying newly developed molecular and computational tools on existing data can provide answers to previously undiagnosed families, Pehlivan said.

Importantly, we also found an explanation for the diagnostic challenge presented by conditions with characteristics that do not match what has been reported in the medical literature, said Mitani, currently at Jichi Medical University, Tokyo, Japan. We determined that the accumulation of particular combinations of rare disease-causing gene mutations at multiple genes, a phenomenon called multilocus pathogenic variation, results in complex characteristics unique to each individual.

The original idea that a single disorder is caused by a mutation in a single gene does not explain the variety of complex neurodevelopmental disorders, Pehlivan explained.

In multilocus pathogenic variation, one patient may have multiple mutated genes. For instance, one gene mutation may result in muscle disease and a different gene mutation that leads to brain disease, while in another patient one mutation may affect the kidneys and another the brain.

The accumulation of specific combinations of rare multiple mutated genes results in conditions with complex characteristics that are unique to each individual.

Patients may present with neurodevelopmental disorders that share similarities but also have important differences, which need to be taken into consideration when deciding treatment and when evaluating risk for other family members.

In this study, for the first time we strictly applied a set of criteria to evaluate multilocus pathogenic variation in our patients and found that it was present in 28.9% of the cases in which we established a genetic diagnosis, Pehlivan said. Our findings confirm the value of routinely applying these criteria to assess the contribution of multilocus pathogenic variation to rare neurodevelopmental disorders and again revealed why genomic studies are superior to single gene testing.

The integrated analyses of the genetic and genomic characteristics of each patient enabled the team to improve their ability to reach a diagnosis in many cases, said co-author Dr. Zeynep Coban Akdemir, assistant professor at UT Health School of Public Health-Houston. Most patients with multilocus pathogenic variation are in consanguineous families.

With studies such as this one, we seek to tackle the challenge of finding the cause of currently unexplained rare genetic disorders, said co-author Dr. Jennifer Posey, assistant professor of molecular and human genetics at BCM. Posey also leads the newly launched BCM GREGoR (Genomic Research to Elucidate the Genetics of Rare) program, a part of the NIH-funded GREGoR Consortium.

The researchers comprehensive approach also adds a valuable resource of information to the study of the function of human genes, human biology and molecular mechanisms involved in neurodevelopmental disorders, all of which can lead to improved diagnosis and treatments.

For a complete list of the contributors to this paper, their affiliations and the financial support for the work, see the publication in The American Journal of Human Genetics.

By Ana Mara Rodrguez, Ph.D.

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Researchers make strides identifying genetic causes of rare neurodevelopmental disorders in the Turkish and worldwide populations - Baylor College of...

Drew Endy, PhD, a Stanford bioengineer, is the kind of brilliant that makes your head spin. His ideas come at a mile a minute, each one a potential mini revolution of standard biology, and his excitement for his work is palpable. But, to me, the best part about Endy is his drive to see a mega-mission through: to use bioengineering to change the world for the better, making contentious efforts to innovate with an eye toward solving social, humanitarian and environmental challenges.

In one of my latest Stanford Medicine magazine stories, "How synthetic biology could save us," I speak to Endy about his lofty vision and the research he's conducting to see it through.

If you ask Endy, synthetic biology is a field that aims to "make the making of things" easier. It's a type of science that expands beyond the natural world, creating tools and techniques to support the development of new biology-based innovations -- like new forms of medicine, or an altered crop that can fight pests on its own.

"We tend to think of biology as something that happens to us," Endy said in the story. "But more and more, we are happening to biology. We're in an era, scientifically, where we can express our intentions into the very kernel of life to allow for possibilities that are simply never going to exist otherwise."

One of Endy's big projects is something he calls "the cleanome," a concept rooted in genetics, but with a twist: In a cleanome, all of an organism's non-crucial genetic elements are removed. (Every living thing contains fundamental genes that support its life, in addition to stretches of DNA that are, essentially, garbage.) The goal is to remove genetic fluff, leaving only the core components that allow an organism to survive.

As Endy said in the story:

If you want to build an organism, you want to definitively know what you're working with, and right now part of what bioengineers are working with is ambiguity."

What bioengineering really needs, according to Endy, is certainty as to which genes are needed for a particular organism to survive along with what each gene is doing. ... Establishing a cleanome for key organisms would allow bioengineers to build and create with more certainty and safety, he said.

Endy and the researchers in his lab have other big ideas percolating too, one of which he's dubbed a "fail-safe" -- basically a built-in self destruct button for an engineered organism. Say, for instance, a scientist creates a type of cancer-fighting cell that runs around the body and gobbles up tumor cells. If that cell started to evolve new cell-gobbling abilities, that would be dangerous. A fail-safe construct built into the cell would notice such a change and kill the rogue cell before it kills its healthy neighbors.

During our interviews, I reflected on the enormity of his proposal: A civilization that not only coexists with bioengineering but also depends on it, harnesses it, continually develops it -- even loves it.

"You'd almost have to be some sort of benevolent dictator to truly see it through," I'd joked to him. He sees it a little differently. "Perhaps more like reluctant philosopher king."

Image by David Plunkert

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Saving the world with synthetic biology - Scope - Scope

PARIS--(BUSINESS WIRE)--Regulatory News:

GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible), a biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today announced that clinical data of LUMEVOQ and GS030 gene therapies will be presented at the 125th Annual Meeting of the American Academy of Ophthalmology (AAO) in New Orleans, Louisiana (November 12-15, 2021).

Retina Subspecialty Day @ American Academy of Ophthalmology (AAO)November 12, 2021Morial Convention Center, New Orleans

Jos-Alain Sahel, MD, Co-founder of GenSight Biologics and of the Institut de la Vision (Sorbonne-Universit/Inserm/CNRS), Paris, France, and Distinguished Professor and Chairman of the Department of Ophthalmology at University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, will discuss the reported signs of efficacy from a second patient affected by Retinitis Pigmentosa and treated with GS030 in the Phase I/IIa trial PIONEER. A first case report was published in Nature Medicine in May 2021.

Optogenetics in the Clinic: Safety and Efficacy Updates on the Phase I/II Clinical Trial PIONEER

American Academy of Ophthalmology (AAO)November 12-15, 2021Morial Convention Center, New Orleans

Nancy J. Newman, MD, LeoDelle Jolley Professor of Ophthalmology and Neurology at the Emory University School of Medicine in Atlanta, GA, USA, and the International Coordinating Investigator of the REFLECT Phase III trial of LUMEVOQ, will discuss the findings from the REFLECT trial in the context of Leber Hereditary Optic Neuropathy (LHON) natural history and the two other clinical trials RESCUE and REVERSE.

The Phase 3 REFLECT Trial: Efficacy and Safety of Bilateral Gene Therapy for LHON

Sean P. Donahue, MD, PhD, Coleman Professor and Vice Chair for Clinical Affairs, and Chief, Pediatric Ophthalmology Department at the Vanderbilt Childrens Hospital in Nashville, TN, USA, and an International Principal Investigator in the REFLECT Phase III trial of LUMEVOQ, will discuss the findings from 6 patients affected by ND4 LHON and bilaterally treated with LUMEVOQ in an FDA-approved compassionate use protocol.

Initial Results From Bilateral Gene Therapy for LHON 11778 Mutation in a Compassionate Use Protocol

About GenSight Biologics

GenSight Biologics S.A. is a clinical-stage biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders. GenSight Biologics pipeline leverages two core technology platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics, to help preserve or restore vision in patients suffering from blinding retinal diseases. GenSight Biologics lead product candidate, LUMEVOQ (GS010; lenadogene nolparvovec), has been submitted for marketing approval in Europe for the treatment of Leber Hereditary Optic Neuropathy (LHON), a rare mitochondrial disease affecting primarily teens and young adults that leads to irreversible blindness. Using its gene therapy-based approach, GenSight Biologics product candidates are designed to be administered in a single treatment to each eye by intravitreal injection to offer patients a sustainable functional visual recovery.

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GenSight Biologics to Present New Clinical Data of LUMEVOQ and GS030 Gene Therapies at the American Academy of Ophthalmology 2021 Meeting - Business...

An assessment of gene therapy ADVM-022 for the treatment of diabetic macular edema (DME) identified dose-dependent safety factors that may influence direction of investigation into the promising therapy in patients with retina diseases.

Findings from the phase 2 INFINITY trial, presented at the American Academy of Ophthalmology (AAO) 2021 Meeting this week by David S. Boyer, MD, Adjunct Clinical Professor of Ophthalmology at USC Keck School of Medicine, contribute to the growing portfolio of ADVM-022 in diabetic ophthalmic disease specifically.

It has already been said that ADVM-022 is a novel biofactory approach to gene therapy, Boyer said. There is a strong, ubiquitous promoter that is designed for robust protein expression, liberating aflibercept from ourselves.

The prior OPTIC study has shown that patients with nAMD previously required frequent injection therapy to maintain vision. Whats more, investigators observed a 97% reduction in mean annualized number of anti-VEGF injections among the 15 patients with nAMD administered 6E11 vg/eye ADVM-022while mean best corrected visual acuity (BCVA) and central subfield thickness (CST) levels were maintained.

OPTIC also showed no patients treated with ADVM-022 reported treatment-related non-ocular adverse events. All treatment-related ocular adverse events were either mild (83%) or moderate (17%) in severity. Ocular inflammation at the 2x1011 vg/eye dose regimen was minimal, and generally resolved with steroid eye drops.

The robust findings of this trial led to the phase 2 INFINITY, in which Boyer and colleagues sought the durability, safety and efficacy of intravitreal ADVM-022 injection in 34 patients with DME. Investigators compared high dose (6x1011 vg/eye), low dose (2x1011), and control for time to worsening of DME disease in the study eye at 24 weeks.

Patients were screened and randomized, then received a loading dose injection of either sham or aflibercept 2 mg. Investigational gene therapy injections were given at day 8.

Over 24 weeks, just 3 (25%) and 5 (39%) patients on high-dose and low-dose ADVM-022 required a supplemental aflibercept injection to address worsening DME at week 24, versus 8 (89%) patients administered aflibercept.

Whats more, nearly half of patients (46%) in each ADVM-022 treatment arm reported a 2 step improvement in diabetic retinopathy severity scale (DRSS) scores at week 12. Another 18% and 36%, respectively, achieved a 3 step improvement by week 24.

That said, more gene therapy-treated patients in the phase 2 trial reported intraocular inflammation: 83% and 92% of the high- and low-dose group, respectively, reported any inflammation, versus just 33% of aflibercept patients. ADVM-022-related adverse events were 57% mild, 41% moderate, and 2% severe.

Across OPTIC and INFINITY, investigators observed dose- and disease state-dependent factors on ADVM-022 efficacy and safety in patients with either nAMD or DME. Boyer stated future development plans for the gene therapy will focus on the treatment of nAMD, and a lower doses.

The difference between the safety seen in OPTIC and INFITIY is being studied, but is unknown, Boyer concluded.

The study, Results From a Phase 2 Study of ADVM-022 Intravitreal Gene Therapy for Diabetic Macula Edema: The INFINITY Trial, was presented at AAO 2021.

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Gene Therapy ADVM-022 Provides Mixed Efficacy, Safety in Treating DME - MD Magazine

Indiana University School of Medicine researchers investigated how the immune cells in the brain -- microglia -- relate to a gene mutation recently found in Alzheimer's disease patients. The findings of the study were published in the journal 'Science Advances'.

The study, led by Hande Karahan, PhD, a postdoctoral fellow in medical and molecular genetics, and Jungsu Kim, PhD, the P. Michael Conneally Professor of Medical and Molecular Genetics, found that deleting the gene -- called ABI3 -- significantly increased amyloid-beta plaque accumulation in the brain and decreased the amount of microglia around the plaques. "This study can provide further insight into understanding the key functions of microglia contributing to the disease and help identify new therapeutic targets," Karahan said.

Karahan based her research on a human genetics study of more than 85,000 people -- fewer than half were Alzheimer's patients -- that identified the mutation in the ABI3 gene. Researchers concluded this mutation increased the risk of late-onset Alzheimer's. "However, there was no investigation into the function of the ABI3 gene in the brain or about how this gene affects microglia function," Karahan said, a fact that led to her research. The team deleted the ABI3 gene from an Alzheimer's disease mouse model and tested the functions of the gene in microglia in cell cultures.

In the mouse model, they saw increased levels of plaques and inflammation in the brain and signs of synaptic dysfunction -- characteristics associated with learning and memory deficits of the disease. Additionally, Karahan said the deletion of the gene impaired the movement of microglia. The immune cells cannot move closer to plaques to try to clear up the proteins.

Amyloid plaques are commonly found in the brains of patients with Alzheimer's; amyloid-beta proteins clump together and form plaques, which destroy nerve cell connections. "Our study provides the first in vivo functional evidence that the loss of ABI3 function may increase the risk of developing Alzheimer's disease by affecting amyloid beta accumulation and neuroinflammation," Karahan said.

Over the past few years, Karahan has been building upon her Alzheimer's disease research. In 2019, Karahan received the Sarah Roush Memorial Fellowship in Alzheimer's Disease Research, established by the Indiana Alzheimer's Disease Research Center and funded through a generous donation from James and Nancy Carpenter and a matching contribution from Stark Neurosciences Research Institute, where Karahan conducts her research. Karahan and Kim received three separate grants supporting this research from the National Institute on Aging, the National Institutes of Health (NIH) branch for Alzheimer's research, resulting in USD 7.8 million over the next five years.

"One grant will fund the creation of a mouse model that will allow us to delete the ABI3 gene in any cell types in the body, such as brain microglia and peripheral immune cells," Kim said. "Once we validate this new model, we will make it available to others in the research community to use this model for their own investigations," Kim added.

The other grants will fund additional mouse and cell models for the team to further investigate how the ABI3 gene in microglia affects Alzheimer's disease pathologies as well as fund state-of-the-art techniques, including brain imaging using the Bruker BioSpec 9.4T PET-MRI scanner, located in the Roberts Translational Imaging Facility at Stark Neurosciences Research Institute. Each of these projects has an end goal of identifying druggable targets for the treatment of the disease, Karahan and Kim said. The team will collaborate with the IU School of Medicine-Purdue TaRget Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) Center. (ANI)

(This story has not been edited by Devdiscourse staff and is auto-generated from a syndicated feed.)

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Role of gene associated with Alzheimer's disease in brain's immune cells investigated by scientists - Devdiscourse