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Nearly 40 patients with a genetic disease that rapidly blinds young adults were successfully treated with gene therapy, according to a paper published today in Science Translational Medicine. The study was conducted by an international team coordinated by Dr. Jos-Alain Sahel from the University of Pittsburgh and Institut de la Vision, Paris, and Dr. Patrick Yu-Wai-Man from the University of Cambridge.

Dr. Jos-Alain Sahel

Surprisingly, scientists found that injecting a gene therapy vector into one eye of someone suffering from Leber hereditary optic neuropathy (LHON) the most common cause of blindness caused by dysfunctional mitochondria in cells of the retina significantly improved vision in both eyes.

LHON is a rapidly progressing genetic disease that causes optic nerve damage and develops in early adulthood. Within a few weeks of disease onset, the vision of most people affected deteriorates to the point where they are considered legally blind.

As someone who treats these young patients, I get very frustrated about the lack of effective therapies, said Sahel, senior investigator of the study and professor and chair of the Department of Ophthalmology at Pitt School of Medicine, as well as director of the UPMC Eye Center. These patients rapidly lose vision in the course of a few weeks to a couple of months. Our study provides a big hope for treating this blinding disease in young adults.

In their effort to correct a genetic error in the mitochondrial DNA a mutation in the gene called MT-ND4 researchers injected an artificial virus containing a template for the correct copy of the gene into the eyes of 37 patients.

We expected vision to improve only in the eyes treated with the gene therapy vector, said international coordinating investigator and neuro-ophthalmologist Yu-Wai-Man, from Cambridges Department of Clinical Neurosciences. Rather unexpectedly, both eyes improved for 78% of patients in the trial following the same trajectory over two years of follow-up.

On average, the best possible vision in treated and untreated eyes improved by three lines of vision 15 and 13 letters on the worldwide standard eye testing chart, respectively. In some patients, the effect was even larger, reaching 28.5 letters for the treated eyes and 24.5 letters for untreated eyes.

To better understand the mechanism by which the treatment of one eye could improve the other, the researchers conducted a study in long-tailed macaques. Macaques have a visual system similar to that of humans, which allows scientists to study the distribution and effects of the gene therapy vector in much greater detail.

The animal study suggested that the gene therapy can reach an untreated eye by passive diffusion traces of the viral vectors genetic material were detected in the back of the untreated eye, including retina and optic nerve.

Our approach isnt just limited to vision restoration, said Sahel. Other mitochondrial diseases could be treated using the same technology.

The technology, called mitochondrial targeting, was developed by the Institut de la Vision in Paris and licensed to GenSight Biologics, a biotech company co-founded by Sahel. The company is seeking marketing authorization from the European Medicines Agency to use its technology as treatment for patients with visual loss due to LHON caused by a confirmed mutation in the ND4 mitochondrial gene.

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Gene Therapy Injection in One Eye Surprises Scientists by Improving Vision in Both - UPMC

DUBLIN--(BUSINESS WIRE)--The "Gene Expression Market By Product And Services, By Capacity, By Application, And Segment Forecasts To 2027" report has been added to ResearchAndMarkets.com's offering.

Increasing demands for cancer medicines, falling cost of sequencing procedures, and a rise in demand for personalized medicines are key factors contributing to the high CAGR of the gene expression market during the forecast period.

The Global Gene Expression Market is expected to reach USD 6.78 billion by the year 2027, in terms of value at a CAGR of 8.1% over the forecast period. Gene expression promises to tap into a previously unexplored segment in the vast and burgeoning genetic engineering industry.

An increase in investments towards technological advancements and a rise in healthcare expenditure are estimated to shape the growth of the gene expression market. Drug discovery & development and increased demand for personalized medicine in chronic diseases, such as cancer, would be the most lucrative applications for gene expression analysis in the forecast period. Application of gene expression in clinical diagnostics, on the other hand, will reflect a moderate growth throughout the analysis period. Moreover, the falling costs of sequencing have facilitated the integration of genomic sequencing into medicine. With the increased availability and lowering costs of DNA technologies, gene expression has become a more readily used tool indispensable in drug discovery and development. Many companies and educational institutions are collaborating to make gene expression publicly accessible through databases, such as the Connectivity Map (CMap), Library of Integrated Network-based Cellular Signatures (LINCS), and the Tox 21 project.

Further key findings from the report suggest:

Key Topics Covered:

Chapter 1. Market Synopsis

Chapter 2. Executive Summary

Chapter 3. Indicative Metrics

Chapter 4. Gene Expression Market Segmentation & Impact Analysis

Chapter 5. Gene Expression Market By Product and Services Insights & Trends

Chapter 6. Gene Expression Market By Capacity Insights & Trends

Chapter 7. Gene Expression Market By Application Insights & Trends

Chapter 8. Gene Expression Market Regional Outlook

Chapter 9. Competitive Landscape

Chapter 10. Company Profiles

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Twenty years ago, President Bill Clinton announced completion of what was arguably one of the greatest advances of the modern era: the first draft sequence of the human genome.

"Without a doubt, this is the most important, the most wondrous map ever produced by humankind," Clinton said on June 26, 2000 from the White House, predicting that genome science "will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases." In the future, he said, "doctors will increasingly be able to cure diseases like Alzheimer's, Parkinson's, diabetes, and cancer by attacking their genetic roots."

And indeed, the sequencing of the human genome achieved simultaneously by the Human Genome Project (HGP), an international consortium begun in 1990 and led by Francis Collins, MD, then director of the National Human Genome Research Institute, and by J. Craig Venter, PhD, with his team at the privately held Celera Genomics has revolutionized the approach to human health.

President Bill Clinton is flanked by Dr J. Craig Venter (left) and Dr Francis Collins announcing the first draft sequence of the human genome in June 2000.

Although the unbridled optimism of 20 years ago has not been matched with success in every quarter, much of the promise has begun to be realized. Scientists have so far identified 5000 rare diseases and 40 to 50 genes that confer cancer risk, developed simple prenatal blood tests to detect chromosomal abnormalities, and generated genetic profiles of tumors to facilitate better-targeted therapies, among other accomplishments. Even the current global fight against COVID-19 is relying on genomics.

"There hasn't been a pharmaceutical developed in last 20 years that hasn't utilized genome information," Venter told Medscape Medical News.

"Not a day goes by in science that we don't see some offshoot of benefit from what happened 20 years ago," said Eric Topol, MD, the chair of innovative medicine at Scripps Research in La Jolla, California, and Editor-in-Chief of Medscape.

Finding the genes was just the beginning though; describing function and using that information therapeutically is still just getting underway in many clinical areas. "We now know that genes are only a small fraction of the complexity of the human genome," says Eric Green, MD, PhD, the current director of the National Human Genome Research Institute (NHGRI).

When it started, the sequencing of the human genome did not seem like a value proposition nor was it expected to be. Congress authorized $3 billion for the HGP in 1990 and set a target completion date of 2005.

The final sequence, a database of some 3 billion DNA base pairs, came in under budget the NHGRI estimates the cost at $2.7 billion in 2003, two years ahead of schedule and exactly 50 years after James Watson and Francis Crick first described DNA.

It had been only 15 months since the international consortium of 1000 researchers across six nations began their sequencing effort in earnest, and a scant 9 months from when Venter's team starting sequencing its human genome. Celera Genomics spent just $100 million, Venter estimates.

What seemed like a massive investment at the time now looks like chicken scratch. "It was a bargain," Topol said.

The race to create the map of the human genome would generate goodwill, create strife, elevate egos, and make careers. Much has been written about the clash between Collins and Venter two polar opposites with different motivations and different approaches.

Collins, a dedicated public servant and man of deep Christian faith, believed in the power of the academic and governmental research enterprise.

Venter, on the other hand, ruffled feathers with his big ideas and generally more capitalistic approach. He began his career at the National Institutes of Health (NIH) in 1984 and created a gene discovery tool called expressed sequence tags (ESTs). That caught the eye of venture capitalists, who lured him out of the agency. They backed Venter's nonprofit, The Institute for Genomic Research (TIGR), to develop the technology.

At TIGR, Venter decoded the genome of Haemophilus influenzae using his whole genome "shotgun" technique. When he applied to the NIH for a grant to support the shotgun method, however, he was rejected. The maker of a DNA sequencing machine, PE Biosystems, then installed Venter as the CEO of the new, private Celera Genomics in 1998.

The NIH-led consortium did not see the value of the shotgun approach and instead relied on a more traditional sequencing method, which was more laborious and time-consuming, Topol recalls. After that NIH rejection, the competition was on, and the rivalry became bitter.

"There was no love lost between these two gentleman," Topol acknowledged. On that day in June 2000 when the announcement was made, "it required Clinton and whoever else to kind of get them to stand together and make nice," added Topol, who was present at the celebration.

A release from the NIH on the commemoration of the 20th anniversary in June of this year describes the situation this way: "The joint presence of these two scientific leaders signified the agreed-upon shared success of the public HGP and private Celera Genomics efforts in generating the first draft sequence of the human genome."

Still, the competition, in retrospect, was a good thing because it accelerated progress, Topol said.

The draft sequence unveiled in 2000 covered 90% of the genome at an error rate of one in 1000 base pairs, but there were more than 150,000 gaps, and only 28% of the genome had reached true completion. When the final version was made public in 2003, there were less than 400 gaps and 99% of the genome was finished with an accuracy rate of less than one error in every 10,000 base pairs.

Looking back, the technologies used then "now seem almost prehistoric," says NHGRI director Green. "Nothing in the way we sequence DNA is the same now. We can do it in a day or two and it costs less than a thousand dollars." He expects the cost of sequencing a human genome will eventually drop below $100.

The final, almost-complete sequence published in 2003 was "foundational," providing "the alphabet around which everything else has been constructed," said Mark McCarthy, MD, senior director and staff scientist in human genetics at the California-based biotechnology company, Genentech. "It's hard to think of a more concrete example in science other than maybe the periodic table," McCarthy told Medscape Medical News.

Doing genetic research before the full sequence was published, he says, was like being an "explorer in some novel land." Without a clear map of the terrain, researchers used analogue methods to try to determine locations of genes or recombination events, he said. It was frustrating and "a huge impediment to progress."

Now, scientists can "just click on a mouse and get almost immediately the worlds of data around any genomic regions," he said.

"Most scientists today never had to sequence a gene," Venter points out. "They don't have to, because they just look it up on the internet."

"Graduate students today can't imagine how we ever did any experiments or learned anything without having access to the human genome sequence with a click of a mouse," said Collins, in a video testimonial celebrating the 30th anniversary of the start of the project.

To Collins, one of the genome project's main goals was to give clinicians better tools to heal their patients. "Together we must develop the advances in medicine, that is the real reason for doing this work," he said in 2000.

If you would have told me that in my professional career I would have seen genomics actually change the practice of medicine in any way, shape, or form, I would have said, 'There's just no way, we're two generations away from that.' Dr Eric Green, director of the National Human Genome Research Institute

But it wasn't until a decade later that genomics was talked about in medicine, said Green. "Now, we have clear examples for genomics being used every day," he said.

"If you would have told me that in my professional career I would have seen genomics actually change the practice of medicine in any way, shape or form, I would have said, 'There's just no way, we're two generations away from that,'" Green said.

Perhaps the biggest impact of these advances in genomics to date has been in the practice of oncology.

"Cancer care has been one of the biggest beneficiaries of the genomic revolution," said Frederick M. Schnell, MD, chief medical officer of the Community Oncology Alliance (COA). Schnell points to the work of Brian Druker, MD, who helped discover the mutation that causes chronic myelogenous leukemia and also was instrumental in developing a precision treatment for CML, imatinib (Gleevec).

"That was probably the singular most important development for a particular, albeit not common, but not uncommon disease that had a disgraceful, horrible projected survival and mortality associated with it, and has changed it to a curable disease," Schnell told Medscape.

The HGP led to the Cancer Genome Atlas, a book of some 20,000 cancer genomes and matched normal samples spanning 33 cancer types.

"In order to understand what was going wrong in a cancer, you first had to understand what the genome was supposed to look like in somebody the cell that was not cancerous," said Richard Schilsky, MD, chief medical officer and executive vice president of the American Society of Clinical Oncology (ASCO).

The comparisons "help us identify mutations that are real drivers of cancer and have opened up the whole field of precision oncology," Schilsky, formerly chief of hematology/oncology and deputy director of the University of Chicago Comprehensive Cancer Center, told Medscape Medical News.

In addition to helping identify cancer susceptibility genes, the genome project also led to variations associated with how drugs are metabolized, Schilsky said.

For instance, it is now known that 10% of the population has a variant of the UGT1A1 gene that leads to poor metabolism of the chemotherapy drug irinotecan (Camptosar), causing worse side effects. The drug's label now notes the availability of a simple lab test to look for the variant.

Schilsky is lead investigator of an ASCO-sponsored trial called TAPUR that aims to match patients with certain tumor variants to therapies that might work, but are not FDA-approved for that particular cancer. Some 2000 individuals have enrolled and received free medications (provided by one of the eight drug companies participating) since the trial began in 2016, said Schilsky.

One goal is to collect evidence on off-label uses which might help therapies gain acceptance in clinical practice guidelines and, potentially, reimbursement. TAPUR also aims to help oncologists learn more about genomics.

Precision oncology is still not available to all cancer patients, however. Schnell said the COA is lobbying for better access and insurance coverage.

He believes that genomics could be used as a replacement for screening tests such as mammograms and colonoscopies. "This is going to be a big application point for the genomic revolution as it continues," he said.

Topol agrees that genomics could create a tailored approach to prevention. "Why does every woman need a mammogram when only 12% will ever develop breast cancer?" he says.

The progress made to date in understanding the human genome is also proving to be a key weapon as scientists fight the important current threat of the COVID-19 pandemic.

China made the first genetic sequence of the SARS-CoV-2 virus available on January 12, 2020, just weeks after the nation reported the initial cluster of cases.

Researchers have since uploaded 245,000 genomic sequences of the SARS-CoV-2 virus to the World Health Organization's Global Initiative on Sharing All Influenza Data (GISAID) portal. The speedy sequencing and widespread sharing of data led to quick development of molecular diagnostics and identification of potential targets for vaccines and therapeutics.

The NHGRI, among others, is supporting genomic studies around the world that aim to understand the differences between those who become severely ill and those "who barely seem to notice they have the disease," NHGRI director Green told Medscape Medical News. "There is no question there is going to be some genomic basis for the severity of the disease,"

He also expects genomics to be used in vaccine trials to separate responders from nonresponders.

While rare monogenic diseases were a relative cinch, common illnesses like hypertension, diabetes, and Alzheimer's disease have turned out to be more complicated.

It wasn't until the mid-2000s, when genome-wide association studies (which look for small variations that occur more frequently in people with disease) came into greater use, that scientists began to get a clearer picture, said Genentech's McCarthy.

It turns out that "hundreds, if not thousands of genetic variations and genetic regions" seem to predispose someone to a common disease, he said. He's applying genome-wide approaches in type 2 diabetes, but it requires datasets of a million or more people to get a robust result, McCarthy said.

Even then, "it just gives you a bunch of sign posts around the genome and then you have to work out what they do and how they influence predisposition in a given individual," he said. Researchers have begun to understand "the range of pathways and networks that are involved in the genetic predisposition to type 2 diabetes," which in turn is giving information on potential therapeutic targets.

The obstacle is not having enough genome-wide genetic data, which may change as more countries find ways to collect more genetic data, McCarthy said.

"We're not getting complete comprehensive views of all the genes involved and all the genomic variants that confer risk," for chronic diseases, agreed Green. "That's the big challenge for the next decade."

Another challenge that NHGRI has outlined in its strategic plan, released in October, is broadening human genome reference databases to include a wider representation of humanity. "Much like all other scientific disciplines, genomics is reckoning with systematic injustice and biases of the past," the agency said in a press release. The plan also addresses data control, privacy, genome editing, and barriers to a thriving genomics enterprise.

Venter believes that getting to the root of chronic diseases means combining the phenotype with the genotype. In 2013, he started Human Longevity, a company that offers sequencing, imaging, and a host of diagnostics to those who can afford the service, to give a complete picture.

"Without extensive phenotype information, the genome isn't highly useful on its own," said Venter, who feels the combination could be a true preventive medicine platform.

As much as the sequencing of the genome has brought to medicine, "I think the greatest promise of the genome remains to be realized," said Venter.

The initial focus was on genes. Humans, it turns out, have only 20,000 genes, not that many more than worms or fruit flies. But there's more to life outside of those genes, said Green.

The human genome "is a treasure chest, but we have only gotten a limited number of the keys so far," said Topol. "It is not nearly as informative as it could be."

And genomics still has the potential to do harm an issue that gets periodic scrutiny by commissions and the public. On that day in 2000 at the White House, Venter noted that a just-released poll had reported that 46% of Americans believed that "the impact of the Human Genome Project will be negative."

Privacy of genetic information is a perennial concern, and technologies such as gene editing, which allows scientists to alter DNA have brought up new ethical challenges.

On the other hand, the public has been mesmerized by genetic genealogy technologies that allow them to determine their own ancestry or disease risk, and that have more recently helped law enforcement solve crimes, some of them longstanding cold cases.

Twenty years ago, Venter predicted that the wonders would continue unabated. "The complexities and wonder of how the inanimate chemicals that are our genetic code give rise to the imponderables of the human spirit should keep poets and philosophers inspired for the millenniums," he said in 2000.

His view is more tempered today. "I'm optimistic about the future," says Venter now. "I'm pessimistic about how soon it will get here."

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The 'Wondrous Map': Charting of the Human Genome, 20 Years Later - Medscape

One of the ways scientists hope to offer better treatments for vision loss is through gene therapy, where carefully selected genetic material is injected into the eyes to address mutations. Researchers have been left surprised by the effectiveness of an experimental form of this treatment, which involved an injection into one eyeball yet improved vision across both.

Gene therapies have the potential to treat all kinds of health conditions, ranging from cancer, to diabetes in dogs, to obesity and damaged spinal cords. One area where we're seeing some really exciting progress is in hereditary vision loss, with studies demonstrating the potential of gene therapy to treat color blindness, progressive retinal diseases and glaucoma, with some recently receiving approval from the FDA.

This latest study was conducted by scientists at the University of Cambridge, the University of Pittsburgh and Paris Institut de la Vision, and focuses on a form of inherited vision loss called Leber hereditary optic neuropathy (LHON). This affects around one in 30,000 people and usually occurs in young folks aged in their 20s and 30s, destroying their retinal ganglion cells and in turn the optic nerve. Once the condition takes hold, vision can deteriorate to the point where the subject is considered legally blind in just a matter of weeks, with recovery occurring in less than 20 percent of cases.

The majority of patients suffer from the same mutation affecting the MT-ND4 gene, so the researchers were hopeful of targeting this mutation as a way of improving treatment outcomes for sufferers of LHON. They trialed their gene therapy as part of a study involving 37 patients who had suffered vision loss in the preceding six to 12 months. This meant injecting a viral vector packed with a modified complementary DNA called rAAV2/2-ND4 into the vitreous cavity at the back of just one eye, with a sham treatment injected into the other eye.

We expected vision to improve in the eyes treated with the gene therapy vector only, says study author Dr Yu-Wai-Man. Rather unexpectedly, both eyes improved for 78 percent of patients in the trial following the same trajectory over two years of follow-up.

To investigate the reasons behind this unexpected outcome, the team studied the gene therapys effects in macaques, which have a similar vision system to humans. This enabled them to analyze the tissues from different parts of the eye to see how the viral vector DNA had spread. This provided evidence of interocular diffusion, with the viral vector DNA turning up in the retina, optic nerve and anterior segment of the untreated eye.

As someone who treats these young patients, I get very frustrated about the lack of effective therapies, says senior investigator Dr Sahel, from the University of Pittsburgh. These patients rapidly lose vision in the course of a few weeks to a couple of months. Our study provides a big hope for treating this blinding disease in young adults.

The research was published in the journal Science Translational Medicine.

Source: University of Cambridge

See the article here:
Single gene therapy injection surprisingly boosts vision in both eyes - New Atlas

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

GenSight Biologics (Paris:SIGHT) (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 the journal Science Translational Medicine has published results from the REVERSE pivotal Phase III clinical trial of LUMEVOQ gene therapy in ND4 Leber Hereditary Optic Neuropathy (LHON) subjects along with key results from a non-human primate study investigating the contralateral effect of the gene therapy. The paper*, published in the December issue under the title Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy, is the first peer-reviewed article based on Phase III clinical trial data to document sustained and clinically meaningful bilateral improvement in visual outcomes from a unilateral injection of a gene therapy.

The findings from the REVERSE trial and the non-human primate study were key components of the data package submitted by GenSight Biologics in September 2020 to the European Medicines Agency when it applied for marketing authorization for LUMEVOQ as treatment for patients with visual loss due to LHON caused by a confirmed mutation in the ND4 mitochondrial gene. The agencys decision is expected in Q4 2021.

The treatment has been shown to be safe and the outcomes can be life changing, said Dr. Patrick Yu-Wai-Man, MD, PhD, lead author, REVERSE principal investigator and Senior Lecturer and Honorary Consultant Ophthalmologist at the University of Cambridge, Moorfields Eye Hospital, and the UCL Institute of Ophthalmology, London, United Kingdom.

Our study provides great hope for treating this blinding disease in young adults, said Dr. Jos-Alain Sahel, MD, co-corresponding author, co-founder of GenSight and Director of the Institut de la Vision (Sorbonne-Universit/Inserm/CNRS), Paris, France, where LUMEVOQs underlying mitochondrial targeting technology was developed. Our approach isnt just limited to vision restoration: other mitochondrial diseases could be treated using the same technology, added Dr. Sahel, who is also Chairman of the Department of Ophthalmology at Centre Hospitalier National dOphtalmologie des XV-XX, Paris, France, and Professor and Chairman of the Department of Ophthalmology at the University of Pittsburgh School of Medicine and UPMC (University of Pittsburgh Medical Center), USA.

REVERSE Trial outcomes

37 ND4 LHON subjects, who experienced onset of vision loss from 6 months to one year before enrollment, participated in the REVERSE trial. The results show a clinically meaningful improvement over baseline of +15 ETDRS letters (0.308 LogMAR) in the average best-corrected visual acuity (BCVA) of injected eyes of the 37 REVERSE patients 96 weeks after treatment. The patients other eye, which received a sham injection, experienced an average visual acuity gain over baseline of +13 letters equivalent (0.259 LogMAR). Against nadir, or the worst recorded BCVA, the gains were even more impressive, at +28.5 ETDRS letters for the LUMEVOQ-injected eyes and +24.5 ETDRS letters for sham-injected eyes.

81% of subjects showed a clinically relevant recovery (CRR) from the nadir in one or both eyes. CRR, a measure of treatment response established by an international consensus meeting on the management of LHON1, is defined as either an improvement from off-chart BCVA to on-chart, or an on-chart improvement BCVA of at least -0.2 LogMAR, or +10 ETDRS letters.

The improvement in quality of life metrics relative to baseline values taken before treatment, which were evaluated using the well-established National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), was compelling and largely above the thresholds of clinical relevance. The composite NEI VFQ-25 score showed a mean improvement of 9.5 points, exceeding the clinically relevant threshold of +3.9-+4.3 points.2

Non-human primate study outcomes

The non-human primate study, launched to investigate the mechanism behind the unexpected improvement in the contralateral eyes visual function, was designed to mimic the REVERSE trial, with monkeys given a unilateral LUMEVOQ injection. The study demonstrated the transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the noninjected eye. This result, the authors conclude, provides a plausible mechanistic explanation for the bilateral improvement in visual function after unilateral LUMEVOQ injection.

Other topics discussed

The paper also presents detailed safety data, which document the overall good safety profile of LUMEVOQ, with no viral vector biodissemination and mostly mild ocular adverse events that were controlled with local topical therapy. Additionally, the authors discuss other results from REVERSE, such as other responder analyses and visual outcomes, and place these in context against the natural history insights found in analyses of visual acuity in non-treated patients.

The paper can be obtained from http://www.sciencemag.org.

*About the paper:

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy

Authors: Patrick Yu-Wai-Man1,2,3,4, Nancy J. Newman5, Valerio Carelli6,7, Mark L. Moster8, Valerie Biousse5, Alfredo A. Sadun9, Thomas Klopstock10,11,12, Catherine Vignal-Clermont13,14, Robert C. Sergott8, Gnther Rudolph15, Chiara La Morgia6,7, Rustum Karanjia9,16, Magali Taiel17, Laure Blouin17, Pierre Burguire17, Gerard Smits18, Caroline Chevalier17, Harvey Masonson18, Yordak Salermo18, Barrett Katz18, Serge Picaud19, David J. Calkins20, Jos-Alain Sahel14,19,21,22

Affiliations:

1 Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK.2 Cambridge Eye Unit, Addenbrookes Hospital, Cambridge University Hospitals, Cambridge CB2 0QQ, UK.3 Moorfields Eye Hospital, London EC1V 2PD, UK.4 UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.5 Departments of Ophthalmology, Neurology and Neurological Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA.6 IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, 40139 Bologna, Italy.7 Unit of Neurology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40139 Bologna, Italy.8 Departments of Neurology and Ophthalmology, William H. Annesley, Jr. EyeBrain Center, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, PA 19107, USA.9 Doheny Eye Institute and UCLA School of Medicine, Los Angeles, CA 90086, USA.10 Friedrich Baur Institute at the Department of Neurology, University Hospital, LMU Munich, 80336 Munich, Germany.11German Center for Neurodegenerative Diseases (DZNE), 80336 Munich, Germany.12 Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.13 Department of Neuro-Ophthalmology and Emergencies, Rothschild Foundation Hospital, 75019 Paris, France.14 Centre Hospitalier National dOphtalmologie des Quinze Vingts, FOReSIGHT, INSERM-DGOS CIC 1423, 75012 Paris, France. 15Department of Ophthalmology, University Hospital, LMU Munich, 80336 Munich, Germany.16 Ottawa Hospital Research Institute and University of Ottawa Eye Institute, Ottawa, Ontario K1H 8L6, Canada.17 GenSight Biologics, 75012 Paris, France.18 GenSight Biologics, New York, NY 10016, USA.19 Sorbonne Universit, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.20 The Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.21 Fondation Ophtalmologique A. de Rothschild, 25-29 Rue Manin, 75019 Paris, France.22 Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Notes:

1 V. Carelli, M. Carbonell, I. F. de Coo, A. Kawasaki, T. Klopstock, W. A. Lagrze, C. La Morgia, N. J. Newman, C. Orssaud, J. W. R. Pott, A. A. Sadun, J. van Everdingen, C. Vignal-Clermont, M. Votruba, P. Yu-Wai-Man, P. Barboni, International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J. Neuroophthalmol. 37, 371381 (2017).2 I. J. Suer, G. T. Kokame, E. Yu, J. Ward, C. Dolan, N. M. Bressler, Responsiveness of NEI VFQ-25 to changes in visual acuity in neovascular AMD: Validation studies from two phase 3 clinical trials. Invest. Ophthalmol. Vis. Sci. 50, 36293635 (2009).

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.

About Leber Hereditary Optic Neuropathy (LHON)

Leber Hereditary Optic Neuropathy (LHON) is a rare maternally inherited mitochondrial genetic disease, characterized by the degeneration of retinal ganglion cells that results in brutal and irreversible vision loss that can lead to legal blindness, and mainly affects adolescents and young adults. LHON is associated with painless, sudden loss of central vision in the 1st eye, with the 2nd eye sequentially impaired. It is a symmetric disease with poor functional visual recovery. 97% of patients have bilateral involvement at less than one year of onset of vision loss, and in 25% of cases, vision loss occurs in both eyes simultaneously. The estimated incidence of LHON is approximately 800-1,200 new patients who lose their sight every year in the United States and the European Union.

About LUMEVOQ (GS010)

LUMEVOQ (GS010) targets Leber Hereditary Optic Neuropathy (LHON) by leveraging a mitochondrial targeting sequence (MTS) proprietary technology platform, arising from research conducted at the Institut de la Vision in Paris, which, when associated with the gene of interest, allows the platform to specifically address defects inside the mitochondria using an AAV vector (Adeno-Associated Virus). The gene of interest is transferred into the cell to be expressed and produces the functional protein, which will then be shuttled to the mitochondria through specific nucleotidic sequences in order to restore the missing or deficient mitochondrial function. LUMEVOQ was accepted as the invented name for GS010 (lenadogene nolparvovec) by the European Medicines Agency (EMA) in October 2018.

About RESCUE and REVERSE

RESCUE and REVERSE are two separate randomized, double-masked, sham-controlled Phase III trials designed to evaluate the efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in subjects affected by LHON due to the G11778A mutation in the mitochondrial ND4 gene.

The primary endpoint measured the difference in efficacy of GS010 in treated eyes compared to sham-treated eyes based on BestCorrected Visual Acuity (BCVA), as measured with the ETDRS at 48 weeks post-injection. The patients LogMAR (Logarithm of the Minimal Angle of Resolution) scores, which are derived from the number of letters patients read on the ETDRS chart, was used for statistical purposes. Both trials were adequately powered to evaluate a clinically relevant difference of at least 15 ETDRS letters between treated and untreated eyes adjusted to baseline.

The secondary endpoints involved the application of the primary analysis to bestseeing eyes that received GS010 compared to those receiving sham, and to worseseeing eyes that received GS010 compared to those that received sham. Additionally, a categorical evaluation with a responder analysis was evaluated, including the proportion of patients who maintain vision (< ETDRS 15L loss), the proportion of patients who gain 15 ETDRS letters from baseline and the proportion of patients with Snellen acuity of >20/200. Complementary vision metrics included automated visual fields, optical coherence tomography, and color and contrast sensitivity, in addition to quality of life scales, biodissemination and the time course of immune response. Readouts for these endpoints were at 48, 72 and 96 weeks after injection.

The trials were conducted in parallel, in 37 subjects for REVERSE and 39 subjects for RESCUE, in 7 centers across the United States, the UK, France, Germany and Italy. Week 96 results were reported in 2019 for both trials, after which patients were invited to a long-term follow-up study that will last for three years.

ClinicalTrials.gov Identifiers:REVERSE: NCT02652780RESCUE: NCT02652767

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GenSight Biologics Announces Publication of Results from LUMEVOQ REVERSE Pivotal Phase III Trial and Non-Human Primate Study in Science Translational...

Figure 1

Remaining Lifetime Risk for ATM PV Carriers

SALT LAKE CITY, Dec. 11, 2020 (GLOBE NEWSWIRE) -- In a spotlight poster discussion at the 2020 San Antonio Breast Cancer Symposium (SABCS), Myriad Genetics (NASDAQ: MYGN), a global leader in molecular diagnostics and precision medicine, today presented a new study that shows how its myRisk Hereditary Cancer and riskScore tests can better inform individualized clinical screening and prevention strategies for women at risk of developing breast cancer. The new Myriad study highlights how riskScore, a proprietary tool used to evaluate a womans risk of developing breast cancer, can accurately provide breast cancer risk information into a personalized assessment model for women carrying a pathogenic variant (PV) in the ATM gene.

This new study will enable a highly personalized risk calculation for patients who carry mutations in the ATM gene, said Nicole Lambert, president of Myriad Genetic Laboratories. As a result, women carrying gene mutations will be able to make more informed choices about how to manage their risk; if increased surveillance is sufficient or if they would consider surgical options.

Myriads riskScore test combines data from 20 years of genome-wide association studies with a validated algorithm that uses personal and family history. riskScore is performed in conjunction with Myriads myRisk Hereditary Cancer test, where myRisk identifies people who carry specific cancer-linked genetic mutations.

Asummary of the study is below. Follow Myriad on Twitter via @myriadgenetics and keep up to date with SABCS meeting news and updates by using the #SACBS20 hashtag.

riskScore Poster at SABCS Title: Development of a breast cancer risk assessment model for ATM mutation carriers incorporating Tyrer-Cuzick and a polygenic risk score Program Number: PD10-09 Session Title: Spotlight Poster Discussion 10 This study highlights the development of a comprehensive breast cancer risk model for ATM PV carriers incorporating an 86-variant PRS, along with family history and clinical information captured by Tyrer-Cuzick (a tool used to calculate the risk of breast cancer). The study found that with ATM PV carriers (N=216), a comprehensive model allowed for differentiation of carriers into low, moderate, and high breast cancer risk categories (See figure 1 below).

To view Figure 1. Remaining Lifetime Risk for ATM PV Carriers, please visit the following link:https://www.globenewswire.com/NewsRoom/AttachmentNg/d77da35a-714a-41f4-8a8a-dd79a79dc644

AboutriskScore riskScore is a clinically validated personalized medicine tool that enhances Myriads myRisk Hereditary Cancer test. riskScore helps to further predict a womens lifetime risk of developing breast cancer using clinical risk factors and genetic markers throughout the genome. The test incorporates data from more than 80 single nucleotide polymorphisms identified through 20 years of genome wide association studies in breast cancer and was prospectively validated in our laboratory to predict breast cancer risk in women of European descent. This data is then combined with a personal history and family history algorithm, the Tyrer-Cuzick model, to provide an individualized breast cancer risk assessment. Myriad is committed to advancing the validation of risk-assessment tools and making them available to all women, regardless of ancestry.

About Myriad myRisk Hereditary Cancer The Myriad myRisk Hereditary Cancer test uses an extensive number of sophisticated technologies and proprietary algorithms to evaluate 35 clinically significant genes associated with eight hereditary cancer sites including: breast, colon, ovarian, endometrial, pancreatic, prostate and gastric cancers and melanoma.

About Myriad Genetics Myriad Genetics Inc., is a leading personalized medicine company dedicated to being a trusted advisor transforming patient lives worldwide with pioneering molecular diagnostics. Myriad discovers and commercializes molecular diagnostic tests that: determine the risk of developing disease, accurately diagnose disease, assess the risk of disease progression, and guide treatment decisions across six major medical specialties where molecular diagnostics can significantly improve patient care and lower healthcare costs. Myriad is focused on three strategic imperatives: transitioning and expanding its hereditary cancer testing markets, diversifying its product portfolio through the introduction of new products and increasing the revenue contribution from international markets. For more information on how Myriad is making a difference, please visit the Company's website:www.myriad.com.

Myriad, the Myriad logo, BART, BRACAnalysis, Colaris, Colaris AP, myPath, myRisk, Myriad myRisk, myRisk Hereditary Cancer, myChoice, myPlan, BRACAnalysis CDx, Tumor BRACAnalysis CDx, myChoice CDx, Vectra, Prequel, Foresight, GeneSight, riskScore and Prolaris are trademarks or registered trademarks of Myriad Genetics, Inc. or its wholly owned subsidiaries in the United States and foreign countries. MYGN-F, MYGN-G.

Safe Harbor Statement This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements related to the Company building ATM status into a clinically validated risk assessment tool that will create a more comprehensive, highly personalized report for patients seeking to understand their risk of developing breast cancer; and the Companys strategic directives under the caption "About Myriad Genetics." These "forward-looking statements" are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by forward-looking statements. These risks and uncertainties include, but are not limited to: uncertainties associated with COVID-19, including its possible effects on our operations and the demand for our products and services; our ability to efficiently and flexibly manage our business amid uncertainties related to COVID-19; the risk that sales and profit margins of our molecular diagnostic tests and pharmaceutical and clinical services may decline; risks related to our ability to transition from our existing product portfolio to our new tests, including unexpected costs and delays; risks related to decisions or changes in governmental or private insurers reimbursement levels for our tests or our ability to obtain reimbursement for our new tests at comparable levels to our existing tests; risks related to increased competition and the development of new competing tests and services; the risk that we may be unable to develop or achieve commercial success for additional molecular diagnostic tests and pharmaceutical and clinical services in a timely manner, or at all; the risk that we may not successfully develop new markets for our molecular diagnostic tests and pharmaceutical and clinical services, including our ability to successfully generate revenue outside the United States; the risk that licenses to the technology underlying our molecular diagnostic tests and pharmaceutical and clinical services and any future tests and services are terminated or cannot be maintained on satisfactory terms; risks related to delays or other problems with operating our laboratory testing facilities and our healthcare clinic; risks related to public concern over genetic testing in general or our tests in particular; risks related to regulatory requirements or enforcement in the United States and foreign countries and changes in the structure of the healthcare system or healthcare payment systems; risks related to our ability to obtain new corporate collaborations or licenses and acquire new technologies or businesses on satisfactory terms, if at all; risks related to our ability to successfully integrate and derive benefits from any technologies or businesses that we license or acquire; risks related to our projections about our business, results of operations and financial condition; risks related to the potential market opportunity for our products and services; the risk that we or our licensors may be unable to protect or that third parties will infringe the proprietary technologies underlying our tests; the risk of patent-infringement claims or challenges to the validity of our patents or other intellectual property; risks related to changes in intellectual property laws covering our molecular diagnostic tests and pharmaceutical and clinical services and patents or enforcement in the United States and foreign countries, such as the Supreme Court decisions in Mayo Collab. Servs. v. Prometheus Labs., Inc., 566 U.S. 66 (2012), Assn for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013), and Alice Corp. v. CLS Bank Intl, 573 U.S. 208 (2014); risks of new, changing and competitive technologies and regulations in the United States and internationally; the risk that we may be unable to comply with financial operating covenants under our credit or lending agreements; the risk that we will be unable to pay, when due, amounts due under our credit or lending agreements; and other factors discussed under the heading "Risk Factors" contained in Item 1A of our most recent Annual Report on Form 10-K for the fiscal year ended June 30, 2020, which has been filed with the Securities and Exchange Commission, as well as any updates to those risk factors filed from time to time in our Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. All information in this press release is as of the date of the release, and Myriad undertakes no duty to update this information unless required by law.

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New Study Provides Personalized Breast Cancer Risk Information for Women with ATM Gene Mutations - GlobeNewswire

As the precision medicine field evolves and the science behind personalized therapies for complex conditions surges ahead, reimbursement models are racing to catch up. Precision medicine treatments, like cell and gene therapies, tend to have high price tags and novel delivery mechanisms. This makes creating effective payment models for these therapies a challenge, but drug developers and payers are working together to create out-of-the-box solutions.

Determining prices for breakthrough cell and gene therapies is a complicated process, said Laura Okpala, director of reimbursement policy at Gilead Sciences, at the MedCity INVEST Precision Medicine conference. Though there is a strong belief that the pricing process needs to be driven by value value means different things to different people. Biopharmaceutical companies, like Gilead Sciences, must consult with various stakeholders, including patients, caregivers and payers, who all have different perspectives on value.

Part of why the pricing is so difficult is because of the inherent complexities in the healthcare system, Okpala said. When we think of traditionally how drugs are paid for, were thinking about chronic treatment, were thinking about treatment over a long, extended period, treatment over and over again, reimbursement every single time, and that adds up.

But when you think about cell and gene therapies, all those costs and all of that treatment happens upfront, she added. And then you get that durable response, up to four years at this point. And that is really a paradigm shift when you think about [a] healthcare system that really isnt set up to deal with that upfront cost and that value delivered over time.

But the upfront payment is just one of many challenges. Mark Trusheim, strategic director of the NEWDIGS initiative at the MIT Center for Biomedical Innovation, said at the virtual conference that there are two more key challenges that arise: the performance uncertainty regarding these therapies, particularly around their durability, and the actuarial uncertainty it causes for payers. Most of these therapies are for rare conditions, so a single high-cost therapy in any given month can have a negative impact on payers income statements.

To combat these challenges, several innovative reimbursement models have been developed.

One is a model based on treatment milestones. Per this model, a certain amount of money is paid upfront, and if the therapy doesnt show the intended effects in certain predetermined timeframes, the drug developer pays back a portion of the initial payment.

[The model allows] some risk sharing between the developer and the payer, so they dont have to argue quite so much up front, Trusheim said. And the actual product performance [resolves] how much [is] finally the net reimbursement or the net price for that therapy.

This model helps manage the different expectations and fears of both parties, he added.

Another is a subscription-based model, which includes a fixed fee for unlimited access to certain therapies, Trusheim explained. Cigna has an insurance product that offers this reimbursement model, where plan members contribute a certain amount each month that is used to pay for therapies as needed. Cigna takes on the risk, guaranteeing that they will provide as much therapy as the members require.

This model is a great example of how payers can manage the actuarial fluctuation that occurs when funding cell and gene therapies, Trusheim said. But it comes with its challenges, because in some cases, its difficult to ascertain the eligible population for a particular therapy especially if there are alternate therapies already available.

But Trusheim is confident that innovation in reimbursement will catch up to clinical innovation in the precision medicine arena.

Were now in an era where innovation in payment structures and approaches are beginning to match the kind of innovation we have in the transformative science for patients, he said. Successfully providing patient access and benefit requires both kinds of innovation, not just scientific innovation. The creativity is there we are going to succeed. Just as the science has succeeded, the payment innovation is also moving forward and having success.

Photo credit: Devrimb, Getty Images

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Innovative payment models to support cell and gene therapies on the rise - MedCity News

Compared to chimpanzees, our closest evolutionary cousins, humans are particularly prone to developing advanced carcinomas the type of tumors that include prostate, breast, lung and colorectal cancers even in the absence of known risk factors, such as genetic predisposition or tobacco use.

A recent study led by researchers at University of California San Diego School of Medicine and Moores Cancer Center helps explain why. The study, published December 9, 2020 in FASEB BioAdvances, suggests that an evolutionary genetic mutation unique to humans may be at least partly to blame.

At some point during human evolution, the SIGLEC12 gene and more specifically, the Siglec-12 protein it produces as part of the immune system suffered a mutation that eliminated its ability to distinguish between self and invading microbes, so the body needed to get rid of it, said senior author Ajit Varki, MD, Distinguished Professor at UC San Diego School of Medicine and Moores Cancer Center. But its not completely gone from the population it appears that this dysfunctional form of the Siglec-12 protein went rogue and has now become a liability for the minority of people who still produce it.

Compared to chimpanzees, our closest evolutionary cousins, humans are particularly prone to developing advanced carcinomas, even in the absence of known risk factors. A UC San Diego study found a potential explanation: Negative evolutionary selection has eliminated the Siglec-12 gene in two-third of the human population, yet for the remaining third, this gene has gone rogue, apparently doubling the risk of advanced cancer. Photo credit: Pixabay

Ajit Varki, who is also co-director of both the Glycobiology Research and Training Center and Center for Academic Research and Training in Anthropogeny, led the study with Nissi Varki, MD, professor of pathology at UC San Diego School of Medicine.

In a study of normal and cancerous tissue samples, the researchers discovered that the approximately 30 percent of people who still produce Siglec-12 proteins are at more than twice the risk of developing an advanced cancer during their lifetimes, compared to people who cannot produce Siglec-12.

Normally, genes that encode such dysfunctional proteins are eliminated by the body over time, and approximately two-thirds of the global human population has stopped producing the Siglec-12 protein. Where the gene still hangs around in humans, it was long thought be of no functional relevance, and there have been very few follow-up studies over the two decades since it was discovered. Meanwhile, chimpanzees still produce functioning Siglec-12.

When Nissi Varkis team set out to detect the Siglec-12 in non-cancerous tissue samples using an antibody against the protein, approximately 30 percent of the samples were positive, as expected from the genetic information. In contrast, the majority of advanced cancer samples from the same populations were positive for the Siglec-12 protein.

Looking at a different population of patients with advanced stage colorectal cancer, the researchers found that more than 80 percent had the functional form of the SIGLEC-12 gene, and those patients had a worse outcome than the minority of patients without it.

These results suggest that the minority of individuals who can still make the protein are at much greater risk of having an advanced cancer, Nissi Varki said.

The researchers also validated their findings in mice by introducing tumor cells engineered to produce Siglec-12. The resulting cancers grew much faster, and turned on many biological pathways known to be involved in advanced cancers, compared to control tumor cells without functioning Siglec-12.

According to Ajit Varki, this information is important because it could be leveraged for future diagnostics and treatments. The team got a jump start by developing a simple urine test that could be used to detect the presence of the dysfunctional protein, and we might also be able to use antibodies against Siglec-12 to selectively deliver chemotherapies to tumor cells that carry the dysfunctional protein, without harming non-cancerous cells, he said.

Additional co-authors of the study include: Shoib S. Siddiqui, Michael Vaill, Raymond Do, Naazneen Khan, Andrea L. Verhagen, Gen-Sheng Feng, UC San Diego; Wu Zhang, Heinz-Josef Lenz, University of Southern California; Teresa L. Johnson-Pais, Robin J. Leach, University of Texas Health Science Center; and Gary Fraser, Charles Wang, Loma Linda University.

Funding for this research came, in part, from the National Institutes of Health (grants R01GM32373, 5U01CA086402, T32GM008666 and DK007202).

Disclosure: Professor Ajit Varki is a scientific advisor to Mablytics Inc., a biotech startup which is developing immunotherapeutics directed against this novel Siglec target in solid tumors. Mablytics has also funded a related research collaboration with UC San Diego led by Nissi Varki.

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Evolution May Be to Blame for High Risk of Advanced Cancers in Humans - UC San Diego Health

Every week there are numerous scientific studies published. Heres a look at some of the more interesting ones.

Mutation for Huntingtons Disease Linked to Frontotemporal Dementia and ALS

Researchers with the National Institutes of Health/National Institute of Neurological Disorders And Stroke found that a mutation known to cause Huntingtons disease is linked to frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Huntingtons disease and several other neurological disorders are associated with repeat expansion, a type of mutation that is kind of a genetic stutter, where certain amino acids in the DNA repeat abnormally. Huntingtons disease is the result of a sequence of three amino acids in the huntingtin gene repeats over and over again. The more repeats, the earlier the disease onset.

In a large international project, researchers screened the complete genomes from large cohorts of FTD/ALS patients and compared them to age-matched healthy individuals. Several patients had a well-established genetic marker for FTD/ALS appeared, but what caught everyone off guard was a small subset that had the same huntingtin mutation. They did not demonstrate classical symptoms of Huntingtons, but did for ALS or FTD.

None of these patients symptoms would have clued their physicians into thinking that the underlying genetic cause was related to the repeat expansion we see in Huntingtons disease, said Sonja Scholz, investigator, NINDS Intramural Research Program. Our patients simply dont match a textbook definition of disease when it comes to which mutation produces which symptoms. Here we have patients carrying a pathogenic huntingtin mutation but who present with FTD or ALS symptoms.

There is a theory that since a gene therapy for that mutation is currently in advanced clinical trials, it may have applications to FTD or ALS patients with this particular mutation. There are also possible applications for additional genetic screening for FTD and ALS. The research was published in the journal Neuron.

FDA Report Confirms Pfizer-BioNTechs COVID-19 Vaccine Efficacy

Although not exactly new research, the U.S. Food and Drug Administration (FDA), as part of the first day of its vaccines advisory committee meeting regarding emergency use authorization (EUA) for the Pfizer-BioNTech COVID-19 vaccine, released a 53-page report on Tuesday, December 8, 2020, that summarized data from their candidate vaccine trial. The data supports early data indicating the vaccine is safe and has an efficacy of 95%. The data also outlined how various diversity groups, including people over 65, those with pre-existing medical conditions like diabetes, and Black and/or Hispanic populations, were affected. The results show all appeared to be well protected. Approximately a third of the participants met the definition of obesity, which is lower than the general population of the U.S. The average age of volunteers in the trials was 51.

Eye Drop Designed to Deliver Drugs to the Retina and Other Back-of-the-Eye Tissues

Investigators with the Mass Eye and Ear of the Schepens Eye Research Institute developed an eye drop that can effectively deliver drugs to the retina and other tissues at the back of the eye. The experimental treatment is made up of nanoparticles called eNano-Ro5, and in their preclinical studies delivered a small molecule inhibitor of the transcription factor RUNX1 to the back of the eye. The excessive function of RNX1 has been linked by this same team of scientists to abnormal growth of blood vessels in people with proliferative diabetic retinopathy. In preclinical models reported in 2017, injection of the molecule curbed the aberrant vessel growth. In the new study, they packaged the drug into the nanoparticles and tested them in preclinical models of recurrent retinal detachment and proliferative vitreoretinopathy (PVR). eNano-Ro5 was effective in delivering the drug to the back of the eye, which decreased the severity of PVR.

COVID-19 Virus Particularly Well-Suited to Jump from Animals to Humans

Researchers at Duke University Medical Center studying the origin of SARS-CoV-2, the virus that causes COVID-19, found that it was particularly well-suited to jump from animals to humans. Genetic analysis found that its closest relative was a coronavirus that infects bats, but the ability to jump to humans was tied to a gene fragment from a coronavirus that infects the pangolin, a scaly mammal in Asia. The species-to-species ability to jump is caused by the viruss ability to bind to host cells via changes in its genetic code. However, they found that the typical coronaviruses that infect pangolins are too different from SARS-CoV-2 to have directly caused the pandemic. But they do contain a receptor-binding site that allows the viruses to attach to a cell surface protein common on human respiratory and intestinal epithelial cells, endothelial cell and kidney cells. Although the viral ancestor in the bat is closely related to SARS-CoV-2, its binding site is significantly different, meaning that on its own it cant efficiently infect human cells. They suggest that SARS-CoV-2 is a hybrid virus between bat and pangolin viruses.

Learning More About Which Immune Cells Offer COVID-19 Protection

With the Pfizer-BioNTech, Moderna and AstraZeneca-University of Oxford COVID-19 vaccines either authorized for emergency use or about to in different countries, researchers are still grappling with the exact types of immune responses needed to protect against the disease. Investigators from Beth Israel Deaconess Medical Center, working with monkeys, found that relatively low levels of antibodies offered protection in monkeys against the SARS-CoV-2 virus that causes COVID-19. They also investigated the role of CD8+ T-cells. They found that while antibodies alone can offer protection, including at relatively low levels, T-cells are also helpful if antibody levels are insufficient.

New Insulin Molecule Better Regulates Blood Sugar in Diabetes

Researchers at the University of Copenhagen and biotech company Gubra developed a new insulin molecule that they believe will eventually be able to better control type 1 diabetes. Currently, insulin on the market cannot tell the difference in type 1 diabetic patients if they need a small or large effect from the insulin. The new insulin molecule has a built-in molecular-binding capability that can sense how much blood sugar is in the body. As blood sugar increases, the molecule becomes more active and releases more insulin. As blood sugar decreases, less insulin is released. To date, it has been tested and been proven effective in rats. They are working to engineer the molecule so that it works more quickly and accurately before they can test it in humans.

New Form of Alzheimers Protein in CSF Identified

Investigators with Washington University School of Medicine discovered a novel form of tau, one of two proteins associated with Alzheimers disease (the other is beta-amyloid). The new type is MTBR tau, and the researchers believe it can be used to identify what stage of Alzheimers the person is in and track the progression of the disease. MTBR stands for microtubule-binding region tau. The disease starts when beta-amyloid begins forming plaques in the brain. This stage can last two decades or more without signs of cognitive decline. But soon afterward, tau tangles start to spread in the neurons, and the cognitive issues begin to appear and progress. The tau tangles can be detected by PET brain scans, but they are time-consuming and expensive. The study was published in the journal Brain.

The MTBR tau fluid biomarker measures tau that makes up tangles and can confirm the stage of Alzheimers disease by indicating how much tau pathology is in the brains of Alzheimers disease patients, said Randall J. Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington School of Medicine in St. Louis. If we can translate this into the clinic, wed have a way of knowing whether a persons symptoms are due to tau pathology in Alzheimers disease and where they are in the disease course, without needing to do a brain scan.

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Research Roundup: Huntington's Mutation Linked to Frontotemporal Dementia and ALS and More - BioSpace

A new molecular probe from Stanford University could help reveal how our brains think and remember. This tool, called Fast Light and Calcium-Regulated Expression or FLiCRE (pronounced flicker), can be sent inside any cell to perform a variety of research tasks, including tagging, recording and controlling cellular functions.

Stanford researchers have developed and tested a new molecular probe, called Fast Light and Calcium-Regulated Expression or FLiCRE (pronounced flicker), which could help scientists map and control neural activity. (Image credit: Getty Images)

This work gets at a central goal of neuroscience: How do you find the system of neurons that underlie a thought or cognitive process? Neuroscientists have been wanting this type of tool for a long time, said Alice Ting, professor of genetics in the Stanford School of Medicine and of biology in the School of Humanities and sciences, whose team co-led this work with the lab of Stanford psychiatrist and bioengineer, Karl Deisseroth.

In proof-of-concept experiments, detailed in a paper published Dec. 11 in Cell, the researchers used FLiCRE to take a snapshot of neural activity associated with avoidance behavior in mice. By coupling the FLiCRE snapshot with RNA sequencing, they discovered that these activated neurons primarily belonged to a single cell type, which was inaccessible using genetic tools alone. They then used FLiCRE in combination with an opsin a protein for controlling neural activity with light developed by Deisseroth to reactivate those same neurons a day later, which led the mice to avoid entering a certain room. The brain region the researchers studied, called the nucleus accumbens, is thought to play an important role in human psychiatric diseases, including depression.

FLiCRE is made up of two chains of molecular components that respond to the presence of blue light and calcium. This light sensitivity allows the researchers to precisely control the timing of their experiments, and calcium is an almost-universal indicator of cell activity. To get FLiCRE inside a cell, the researchers package it, in two parts, within a harmless virus. One part of FLiCRE attaches to the cell membrane and contains a protein that can enter the cells nucleus and drive expression of whatever gene the researchers have selected. The other part of FLiCRE is responsible for freeing the protein under certain specific conditions, namely if the concentration of calcium is high and the cell is bathed in blue light.

Whereas existing tagging techniques require hours to activate, the FLiCRE tagging process takes just minutes. The researchers also designed FLiCRE so that they can use standard genetic sequencing to find the cells in which FLiCRE activated. This allows them to study tens of thousands of cells at once, while other techniques tend to require the analysis of multiple microscopic images that each contain hundreds of cells.

In one series of experiments, the researchers injected FLiCRE into cells in the nucleus accumbens and used an opsin to activate a neural pathway associated with avoidance behavior in the mice. Once the calcium in FLiCRE-containing cells spiked the cellular indication that the mouse is avoiding something the cells glowed a permanent red that was visible through a microscope. The researchers also sequenced the RNA of the cells to see which ones contained the fluorescent protein, producing a cell-by-cell record of neural activity.

One goal was to map how brain regions are connected to each other in living animals, which is a really hard problem, said Christina Kim, a postdoctoral scholar in genetics at Stanford and co-lead author of the paper. The beauty of FLiCRE is that we can pulse and activate neurons in one region and then record all of the connected downstream neurons. It is a really cool way to look at long-range brain activity connections.

In the next experiments, the researchers used the cellular activity map from the first experiments. They also adjusted FLiCRE so that the protein expressed the opsin protein, which can be controlled by orange light to alter neuronal activity. After activating FLiCRE in the cells, the researchers sent orange light through the fiber optic implant whenever the mice would enter a certain room. In response, the mice steered clear of that room, indicating that FLiCRE had indeed located cells in the brain that drive avoidant behavior.

The development and testing of FLiCRE combined chemistry, genetics, biology and neuroscience, and many specialties within those disciplines. As a result, the tool has a wide range of possible applications, including in cells outside the brain, the researchers say.

I moved to Stanford in 2016 with the hope of being able to carry out extremely interdisciplinary and collaborative projects such as this, said Ting. This project has been one of the most rewarding aspects of my move to Stanford seeing something this challenging and ambitious actually work out.

The researchers are now working on additional versions of FLiCRE, with a goal of streamlining the process. They are hoping to simplify its structure and also make it capable of working with other biochemical events, such as protein interactions or neurotransmitter release.

Mateo Snchez, a former postdoctoral scholar in the Ting lab, is also co-lead author of the paper. Additional authors are Paul Hoerbelt, Lief E. Fenno and Robert Malenka, the Pritzker Professor of Psychiatry and Behavioral Sciences, Director of the Nancy Pritzker Laboratory and Deputy Director of the Wu Tsai Neurosciences Institute. Deisseroth, is the D. H. Chen Professor, and a professor of bioengineering and of psychiatry and behavioral sciences; and a member of Stanford Bio-X and the Wu Tsai Neurosciences Institute. Ting is a member ofStanford Bio-X, the Maternal & Child Health Research Institute (MCHRI), theStanford Cancer Institute and the Wu Tsai Neurosciences Institute, and a faculty fellow ofStanford ChEM-H.

This research was funded by the Walter V. and Idun Berry Postdoctoral Fellowship Program, the EMBO long-term postdoctoral fellowship, the National Institute of Mental Health, Stanford Psychiatry, the Wu Tsai Neurosciences Institute, the National Institute on Drug Abuse, the Defense Advanced Research Projects Agency Neuro-FAST program, the NOMIS Foundation, the Wiegers Family Fund, the Nancy and James Grosfeld Foundation, the H. L. Snyder Medical Foundation, the Samuel and Betsy Reeves Fund, the Gatsby Foundation, the AE Foundation, the Fresenius Foundation and the Chan Zuckerberg Biohub.

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LA JOLLA, Calif.--(BUSINESS WIRE)--DermTech, Inc. (NASDAQ: DMTK) (DermTech), a leader in precision dermatology enabled by a non-invasive skin genomics platform, announced today its inclusion in two CME sessions, at the Fall Clinical Dermatology Virtual Grand Rounds (the FCVGR) and the 23rd Annual Mount Sinai Winter Symposium Advances in Medical and Surgical Dermatology (the Mount Sinai Symposium).

The FCVGR presentation was led by Laura K Ferris, MD, PhD of the University of Pittsburgh Department of Dermatology on December 2. The Mount Sinai Symposium presentation was led by George Han, MD, Chairman of the Department of Dermatology at Mount Sinai Beth Israel, on December 4, 2020.

Fall Clinical Dermatology Virtual Grand Rounds

The co-directors of the Fall Clinical Dermatology Conference created the Virtual Grand Round series to help meet the continued need for CME accreditation during uncertain times and maintain the educational opportunities that would traditionally be available at an in-person conference.

Dr. Ferris led the CME presentation Gene Expression Profiling for Melanoma Diagnosis, during the Evolving Concepts in Dermatology Part XVIII, session of the FCVGR. The presentation is available for viewing here.

Dr. Ferris commented in her presentation, New clinical research demonstrates that 78% of lesions that are Pigmented Lesion Assay positive and therefore demonstrate genomic atypia in all cases, also have features of atypia or melanoma histopathologically.

Mount Sinai Winter Symposium

The Mount Sinai Symposium is specifically designed to equally update the practicing dermatologists, cosmetic surgeons and other healthcare professionals on the latest advances in medical and surgical dermatology.

Dr. Han, who serves as the Director of Teledermatology for the Department of Dermatology at the Icahn School of Medicine at Mount Sinai, led the CME presentation in the session Using Genomics for Melanoma Diagnosis.

Dr. Han commented: The current paradigm of evaluating pigmented lesions leaves much to be desired, both in our approach to lesions in clinical practice as well as in obtaining and evaluating biopsies for accurate diagnoses. There is great potential in using genomics to improve our approach to pigmented lesionsand with DermTechs Pigmented Lesion Assay, we can now offer our patients a non-invasive test that improves our current sensitivity towards diagnosing melanoma. That, combined with the fact that we can utilize telemedicine to bring this test into our patients' homes and potentially catch melanomas earlier, gives us the ability to finally make an impact on the diagnosis and mortality rate of melanoma.

About DermTech:

DermTech is the leading genomics company in dermatology and is creating a new category of medicine, precision dermatology, enabled by our non-invasive skin genomics platform. DermTechs mission is to transform the practice of dermatology through more accurate diagnosis and treatment, and the elimination of unnecessary surgery, leading to improved patient care and lower costs. DermTech provides genomic analysis of skin samples collected non-invasively using an adhesive patch rather than a scalpel. DermTech markets and develops products that facilitate the early detection of skin cancers, and is developing products that assess inflammatory diseases and customize drug treatments. For additional information on DermTech, please visit DermTechs investor relations site at: http://www.DermTech.com.

Forward-looking Statements

This press release includes forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. The expectations, estimates, and projections of DermTech may differ from its actual results and consequently, you should not rely on these forward-looking statements as predictions of future events. Words such as expect, estimate, project, budget, forecast, anticipate, intend, plan, may, will, could, should, believes, predicts, potential, continue, and similar expressions are intended to identify such forward-looking statements. These forward-looking statements include, without limitation, expectations with respect to: the performance, patient benefits, cost-effectiveness, commercialization and adoption of DermTechs products, including the Pigmented Lesion Assay, and the market opportunity therefor. These forward-looking statements involve significant risks and uncertainties that could cause the actual results to differ materially from the expected results. Most of these factors are outside of the control of DermTech and are difficult to predict. Factors that may cause such differences include, but are not limited to: (1) the outcome of any legal proceedings that may be instituted against DermTech; (2) DermTechs ability to obtain additional funding to develop and market its products; (3) the existence of favorable or unfavorable clinical guidelines for DermTechs tests; (4) the reimbursement of DermTechs tests by Medicare and private payors; (5) the ability of patients or healthcare providers to obtain coverage of or sufficient reimbursement for DermTechs products; (6) DermTechs ability to grow, manage growth and retain its key employees; (7) changes in applicable laws or regulations; (8) the market adoption and demand for DermTechs products and services together with the possibility that DermTech may be adversely affected by other economic, business, and/or competitive factors; and (9) other risks and uncertainties included in (x) the Risk Factors section of the most recent Quarterly Report on Form 10-Q filed by DermTech with the Securities and Exchange Commission (the SEC), and (y) other documents filed or to be filed by DermTech with the SEC. DermTech cautions that the foregoing list of factors is not exclusive. You should not place undue reliance upon any forward-looking statements, which speak only as of the date made. DermTech does not undertake or accept any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements to reflect any change in its expectations or any change in events, conditions, or circumstances on which any such statement is based.

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DermTech's Melanoma Test Included in Two Continuing Medical Education (CME) Sessions at 2020 Fall Clinical Virtual Grand Rounds and Mount Sinai Winter...

THURSDAY, Dec. 10, 2020 (HealthDay News) -- Use of the ex vivo CRISPR-Cas9-based gene-editing platform to edit the erythroid enhancer region of BCL11A in hematopoietic stem and progenitor cells, producing CTX001, results in increased hemoglobin (Hb) among patients with transfusion-dependent -thalassemia (TDT) and sickle cell disease (SCD), according to a study published online Dec. 5 in the New England Journal of Medicine to coincide with the annual meeting of the American Society of Hematology, held virtually from Dec. 5 to 8.

Haydar Frangoul, M.D., from the Sarah Cannon Center for Blood Cancer at the Children's Hospital at TriStar Centennial in Nashville, Tennessee, and colleagues presented safety and efficacy results from patients with at least three months of follow-up from two first-in-human studies of CTX001 for TDT and SCD. Data were included for seven patients with TDT and three with SCD.

The researchers found increases in total Hb and fetal Hb among all patients over time. Patients with TDT stopped receiving packed red blood cell transfusions soon after CTX001 infusion; the first patients with TDT who received CTX001 remained transfusion-free for more than 15 months. Since CTX001 infusion, the patients with SCD have had no vaso-occlusive crises (VOCs); the first patient to receive CTX001 remained VOC-free for more than one year. The safety profile after CTX001 infusion was generally consistent with busulfan myeloablation in all 10 patients. One patient with TDT had four serious adverse events related or possibly related to CTX001.

"By gene editing the patient's own stem cells we may have the potential to make this therapy an option for many patients facing these blood diseases," Frangoul said in a statement.

Several authors disclosed financial ties to pharmaceutical companies, including CRISPR Therapeutics and Vertex Pharmaceuticals, which sponsored the trial.

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ASH: CRISPR-Cas9 Gene Editing Promising in TDT, SCD - HealthDay News

Some of the most promising vaccines developed to combat Covid-19 rely on messenger RNA (mRNA) a template cells use to carry genetic instructions for producing proteins. The mRNA vaccines take advantage of this cellular process to make proteins that then trigger an immune response that targets SARS-CoV-2, the virus that causes Covid-19.

Compared to other types of vaccines, recently developed technologies allow mRNA vaccines to be rapidly created and deployed on a large-scale crucial aspects in the fight against Covid-19. Within the year since the identification and sequencing of the SARS-CoV-2 virus, companies such as Pfizer and Moderna have developed mRNA vaccines and run large-scale trials in the race to have a vaccine approved by the U.S. Food and Drug Administration a feat unheard of with traditional vaccines using live attenuated or inactive viruses. These vaccines appear to have a greater than 90 percent efficacy in protecting against infection.

The fact that these vaccines could be rapidly developed within these last 10 months rests on more than four decades of study of mRNA. This success story begins with Institute Professor Phillip A. Sharps discovery of split genes and spliced RNA that took place at MIT in the 1970s a discovery that would earn him the 1993 Nobel Prize in Physiology or Medicine.

Sharp, a professor within the Department of Biology and member of the Koch Institute for Integrative Cancer Research at MIT, commented on the long arc of scientific research that has led to this groundbreaking, rapid vaccine development and looked ahead to what the future might hold for mRNA technology.

Q: Professor Sharp, take us back to the fifth floor of the MIT Center for Cancer Research in the 1970s. Were you and your colleagues thinking about vaccines when you studied viruses that caused cancer?

A: Not RNA vaccines! There was a hope in the 70s that viruses were the cause of many cancers and could possibly be treated by conventional vaccination with inactivated virus. This is not the case, except for a few cancers such as HPV causing cervical cancer.

Also, not all groups at the MIT Center for Cancer Research (CCR) focused directly on cancer. We knew so little about the causes of cancer that Professor Salvador Luria, director of the CCR, recruited faculty to study cells and cancer at the most fundamental level. The centers three focuses were virus and genetics, cell biology, and immunology. These were great choices.

Our research was initially funded by the American Cancer Society, and we later received federal funding from the National Cancer Institute, part of the National Institutes of Health and the National Science Foundation as well as support from MIT through the CCR, of course.

At Cold Spring Harbor Laboratory in collaboration with colleagues, we had mapped the parts of the adenovirus genome responsible for tumor development. While doing so, I became intrigued by the report that adenovirus RNA in the nucleus was longer than the RNA found outside the nucleus in the cytoplasm where the messenger RNA was being translated into proteins. Other scientists had also described longer-than-expected nuclear RNA from cellular genes, and this seemed to be a fundamental puzzle to solve.

Susan Berget, a postdoc in my lab, and Claire Moore, a technician who ran MITs electron microscopy facility for the cancer center and would later be a postdoc in my lab, were instrumental in designing the experiments that would lead to the iconic electron micrograph that was the key to unlocking the mystery of this heterogeneous nuclear RNA. Since those days, Sue and Claire have had successful careers as professors at Baylor College of Medicine and Tufts Medical School, respectively.

The micrograph showed loops that would later be called introns unnecessary extra material in between the relevant segments of mRNA, or exons. These exons would be joined together, or spliced, to create the final, shorter message for the translation to proteins in the cytoplasm of the cell.

This data was first presented at the Cancer Center fifth floor group meeting that included Bob Weinberg, David Baltimore, David Housman, and Nancy Hopkins. Their comments, particularly those of David Baltimore, were catalysts in our discovery. Our curiosity to understand this basic cellular mechanism drove us to learn more, to design the experiments that could elucidate the RNA splicing process. The collaborative environment of the MIT Cancer Center allowed us to share ideas and push each other to see problems in a new way.

Q: Your discovery of RNA splicing was a turning point, opening up new avenues that led to new applications. What did this foundation allow you to do that you couldnt do before?

A: Our discovery in 1977 occurred just as biotechnology appeared with the objective of introducing complex human proteins as therapeutic agents, for example interferons and antibodies. Engineering genes to express these proteins in industrial tanks was dependent on this discovery of gene structure. The same is true of the RNA vaccines for Covid-19: By harnessing new technology for synthesis of RNA, researchers have developed vaccines whose chemical structure mimics that of cytoplasmic mRNA.

In the early 1980s, following isolation of many human mutant disease genes, we recognized that about one-fifth of these were defective for accurate RNA splicing. Further, we also found that different isoforms of mRNAs encoding different proteins can be generated from a single gene. This is alternative RNA splicing and may explain the puzzle that humans have fewer genes 21,000 to 23,000 than many less complex organisms, but these genes are expressed in more complex protein isoforms. This is just speculation, but there are so many things about biology yet to be discovered.

I liken RNA splicing to discovering the Rosetta Stone. We understood how the same letters of the alphabet could be written and rewritten to form new words, new meaning, and new languages. The new language of mRNA vaccines can be developed in a laboratory using a DNA template and readily available materials. Knowing the genetic code of the SARS-CoV-2 is the first step in generating the mRNA vaccine. The effective delivery of vaccines into the body based on our fundamental understanding of mRNA took decades more work and ingenuity to figure out how to evade other cellular mechanisms perfected over hundreds of millions of years of evolution to destroy foreign genetic material.

Q: Looking ahead 40 more years, where do you think mRNA technology might be?

A: In the future, mRNA vaccine technology may allow for one vaccine to target multiple diseases. We could also create personalized vaccines based on individuals genomes.

Messenger RNA vaccines have several benefits compared to other types of vaccines, including the use of noninfectious elements and shorter manufacturing times. The process can scaled up, making vaccine development faster than traditional methods. RNA vaccines can also be moved rapidly into clinical trials, which is critical for the next pandemic.

It is impossible to predict the future of RNA therapies, such as the new vaccines, but there are some signs that new advancements could happen very quickly. A few years ago, the first RNA-based therapy was approved for treatment of lethal genetic disease. This treatment was designed through the discovery of RNA interference. Messenger RNA-based therapies will also likely be used to treat genetic diseases, vaccinate against cancer, and generate transplantable organs. It is another tool at the forefront of modern medical care.

But keep in mind that all mRNAs in human cells are encoded by only 2 percent of the total genome sequence. Most of the other 98 percent is transcribed into cellular RNAs whose activities remain to be discovered. There could be many future RNA-based therapies.

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3 Questions: Phillip Sharp on the discoveries that enabled RNA vaccines for Covid-19 - MIT News

Contour Therapeutics Brings Together Leaders with Extensive Cardiovascular, Genetics and Drug Development Expertise

Partnership Focused on Delivering Targeted Therapies for Genetically Defined Cardiovascular Diseases

PALO ALTO, Calif. and SOUTH SAN FRANCISCO, Calif., Dec. 07, 2020 (GLOBE NEWSWIRE) -- BridgeBio Pharma, Inc. (Nasdaq: BBIO) and Maze Therapeutics today announced the establishment of a joint venture, Contour Therapeutics, focused on transforming and advancing breakthrough precision medicine approaches designed to treat cardiovascular disease, the leading cause of death worldwide.

This joint venture between two leading biotech companies unites Mazes genetically driven approach to drug discovery, as well as insights from its COMPASS platform, with BridgeBios expertise in cardiac drug discovery and clinical development. Together, the companies will focus on advancing genetically validated therapeutic candidates through clinical development and will initially work on the development of a treatment for patients with an undisclosed, genetically defined form of heart failure.

The new partnership builds on exciting progress underway to identify and target genetic causes of cardiovascular diseases, including BridgeBios precision medicine approach at its affiliate Eidos Therapeutics designed to treat transthyretin amyloidosis, an underdiagnosed and life-threatening cause of heart failure. The partnership also builds on seminal advances in the treatment of inherited cardiomyopathies, including at MyoKardia, a company co-founded by senior leaders at BridgeBio and Maze.

Cardiovascular disease is a deadly and widespread health problem across the world, but unfortunately, innovations in new treatment approaches have been limited, said Jason Coloma, Ph.D., CEO of Maze. Since we launched Maze, we have been focused on the advancement of our COMPASS platform, on which weve made important progress and gained confidence in the genetics we are focused on, as well as novel insights into how to best develop therapies for patients with cardiovascular disease. We are excited to join forces with BridgeBio, combining the unique talents and expertise across our respective teams, in order to deliver a profound impact on how these diseases are treated in the future.

We are privileged to be partnering with and learning from Maze. We are eager to build on BridgeBios work in precision medicine to treat cardiovascular disease, and we believe our joint venture with Maze holds great promise for patients as we bring together innovative leaders in cardiology and genetics, said Neil Kumar, Ph.D., founder and CEO of BridgeBio. The identification and targeting of genetically defined patient populations has created elegant and clinically meaningful medicines in oncology and other therapeutic areas. We feel strongly that one of the next frontiers in precision medicine lies in helping people suffering from cardiovascular disease, and we are excited to be on the front lines of advances in this field.

This partnership between Maze and BridgeBio will bring together many of the people who helped found and build revolutionary companies in cardiovascular drug development, said Charles Homcy, M.D., chairman of the Maze board of directors and lead director and chairman of pharmaceuticals of BridgeBio. With the combined expertise of these teams, we have an opportunity to create something special that has a profound impact on how patients with cardiovascular disease are treated in the future.

About the Maze COMPASS PlatformThe Maze COMPASS platform combines human genetics, functional genomics and data science to identify and prioritize drug targets for both rare and common diseases, validate drug targets and inform target tractability and clinical development. Maze aims to leverage COMPASS to translate a wealth of genetic opportunities generated by the platform into new therapeutics.

About Maze Therapeutics Maze Therapeutics is a biopharmaceutical company developing a broad portfolio of therapeutic candidates for a number of genetically defined diseases. Maze is focused on translating genetic insights into new medicines by utilizing an approach that combines the analysis of large-scale human genetics data, cutting-edge functional genomics and an array of drug discovery approaches. The Maze COMPASS platform reveals modifier genes that confer protection and provides deeper understanding of the target biology and how these targets can be best targeted with drug therapies. Maze was launched in 2019 by Third Rock Ventures, with funding from ARCH Venture Partners, GV, Foresite Capital, Casdin Capital, Alexandria Venture Investments, City Hill and other undisclosed investors. Maze is based in South San Francisco. For more information, please visit mazetx.com.

About BridgeBio Pharma, Inc.BridgeBio is a team of experienced drug discoverers, developers and innovators working to create life-altering medicines that target well-characterized genetic diseases at their source. BridgeBio was founded in 2015 to identify and advance transformative medicines to treat patients who suffer from Mendelian diseases, which are diseases that arise from defects in a single gene, and cancers with clear genetic drivers. BridgeBios pipeline of over 20 development programs includes product candidates ranging from early discovery to late-stage development. For more information visit http://www.bridgebio.com.

BridgeBio Pharma Forward-Looking StatementsThis press release contains forward-looking statements. Statements we make in this press release may include statements that are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended (the Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended (the Exchange Act), which are usually identified by the use of words such as anticipates, believes, estimates, expects, intends, may, plans, projects, seeks, should, will, and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements relating to Contour Therapeutics focus on transforming and advancing breakthrough precision medicine approaches designed to treat cardiovascular disease, the joint ventures focus on advancing genetically validated therapeutic candidates through clinical development and its initial work on the development of a treatment for patients with an undisclosed genetically defined form of heart failure, the partnerships ability to identify and target genetic causes of cardiovascular diseases and build on seminal advances in the treatment of inherited cardiomyopathies, the success of and potential synergies from the joint venture between Maze and BridgeBio, Contour Therapeutics development plans, competitive environment and clinical and therapeutic potential of therapies for patients with cardiovascular disease, reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a number of risks, uncertainties and assumptions, including, but not limited to, Contour Therapeutics ability to focus on transforming and advancing breakthrough precision medicine approaches designed to treat cardiovascular disease, the timing and success of advancing genetically validated therapeutic candidates through clinical development and any such continued clinical development and planned regulatory submissions, and the success and potential synergies of the joint venture between Maze and BridgeBio, as well as those risks set forth in the Risk Factors section of BridgeBio Pharmas most recent Annual Report on Form 10-K, Quarterly Report on Form 10-Q and BridgeBio Pharmas other SEC filings. Moreover, BridgeBio Pharma operates in a very competitive and rapidly changing environment in which new risks emerge from time to time. Except as required by applicable law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.

Media ContactsMaze:Katie Engleman, 1AB katie@1abmedia.com

BridgeBio Pharma:Grace Rauh917-232-5478grace.rauh@bridgebio.com

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BridgeBio Pharma and Maze Therapeutics Establish Joint Venture to Advance Precision Medicine to Treat Cardiovascular Disease - GlobeNewswire

WHIPPANY, N.J. & CHICAGO--(BUSINESS WIRE)--Bayer and Tempus, leaders in precision medicine and artificial intelligence (AI), announced a new collaboration designed to provide broader access to genomic testing and tailored treatment approaches for the oncology community. The collaboration will include an initiative to help facilitate patient identification for precision oncology by providing testing, via the Tempus xT broad-panel genomic sequencing assay, for a subset of patients with metastatic colorectal cancer (mCRC), as well as those with radioactive iodine refractory differentiated metastatic thyroid carcinoma (RAIR thyroid cancers). Looking ahead, Bayer and Tempus will continue to implement data-enriched initiatives dedicated to supporting patients.

Bayer's commitment to precision oncology is currently supported by its approach to research that prioritizes targets and pathways that impact the way cancer is treated. The Tempus xT broad-panel genomic sequencing assay is designed to detect actionable driver alterations, including BRAF, KRAS, RET, and NTRK gene fusions.1 NTRK gene fusions are genomic alterations that drive tumor growth regardless of where they originate in the body.2-4 These genomic alterations typically occur following DNA damage, which results in structural changes to the DNA either through biological changes or from environmental factors (e.g. ultraviolet light damage).2-4 During the DNA damage repair mechanism, the NTRK gene can fuse with an unrelated gene resulting in an altered TRK fusion protein, which causes a constant signaling cascade, driving tumor growth and its metastasis (progression).2-4 Studies suggest NTRK gene fusions are present in approximately 3% of patients with mCRC with prior high microsatellite instability (MSI-H) status and 2.4%-12% of patients with RAIR thyroid cancers.5-7

Testing early and utilizing comprehensive genomic profiling is critical, as it helps physicians understand the underlying driver of DNA alterations for tumor progression (growth).8,9 When actionable alterations are detected, they aid physicians in the treatment decisions appropriate for their patients.10 The Tempus xT broad-panel genomic sequencing assay detects these alterations by sequencing tumor samples with matched normal saliva or blood samples, when available, covering 648 genes.1 The test is used by many oncologists across a diverse set of clinical settings, including leading academic centers, NCI designated cancer centers, hospital networks and community hospitals.

Bayers strong focus in precision medicine combined with Tempus unique testing offering has culminated in this collaboration to bring genomic testing to cancer patients, said Bhavesh Ashar, Senior Vice President, Head of U.S. Oncology at Bayer. "We are excited for the potential of this initiative to identify patients who may benefit from tailored treatment options.

"This strategic collaboration aims to provide eligible colorectal and thyroid cancer patients with broad based access to our genomic test to help their physicians make treatment decisions," said Ryan Fukushima, Chief Operating Officer of Tempus.

Healthcare professionals with eligible patients from the above tumor types can receive additional information by learning more at Tempus.com/bayerprogram and contacting Tempus at support@tempus.com.

About Oncology at Bayer

Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now expands to six marketed products and several other assets in various stages of clinical development. Together, these products reflect the companys approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

About Bayer

Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to benefit people by supporting efforts to overcome the major challenges presented by a growing and aging global population. At the same time, the Group aims to increase its earning power and create value through innovation and growth. Bayer is committed to the principles of sustainable development, and the Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2019, the Group employed around 104,000 people and had sales of 43.5 billion euros. Capital expenditures amounted to 2.9 billion euros, R&D expenses to 5.3 billion euros. For more information, go to http://www.bayer.us.

About Tempus

Tempus is a technology company advancing precision medicine through the practical application of artificial intelligence in healthcare. With one of the worlds largest libraries of clinical and molecular data, and an operating system to make that data accessible and useful, Tempus enables physicians to make real-time, data-driven decisions to deliver personalized patient care and in parallel facilitates discovery, development and delivery of optimal therapeutics. The goal is for each patient to benefit from the treatment of others who came before by providing physicians with tools that learn as the company gathers more data. For more information, visit tempus.com.

###

2020 Bayer

BAYER and the Bayer Cross are registered trademarks of Bayer.

Forward-Looking Statements

This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayers public reports which are available on the Bayer website at http://www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

______________________________________________________________________________

References

PP-PF-ONC-US-1620-1

12/20

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Bayer and Tempus Initiate Collaboration to Advance Patient Access to Genomic Testing and Precision Medicine - Business Wire

Identification of key oncogenic drivers and the development of targeted therapies with clinical activity in patients harboring actionable mutations have revolutionized the treatment paradigm in nonsmall cell lung cancer (NSCLC), redirecting attention toward advances in biomarker testing methodologies. This new focus is poised to foster granular refinement of precise, targeted treatment of lung tumors.

Advances in NSCLC research have enabled an understanding of the disease as a collection of molecular subgroups. The proliferation of alteration-matched therapies specific to these subgroups is a prime example of a precision medicine approach. In addition to oncogenic driver mutations, therapeutic response biomarkers have been identified, such as PD-L1 expression as a predictor of immunotherapy efficacy.

Underscoring the importance of biomarker-guided treatment approaches, guidelines for molecular testing in NSCLC include an extensive list of alterations, such as sensitizing EGFR mutations and ALK gene fusions.1,2 The list continues to expand beyond these established canonical markers, with the addition of variants such as MET exon 14 skipping mutations and tumor mutational burden. In fact, the FDA recently approved therapies specific for tumors with these molecular characteristics.3,4

The rapid pace of biomarker discovery, characterization of molecular subtypes of NSCLC, development of matched targeted therapies, and regulatory approval of companion diagnostic tests has accelerated progress in the delivery of optimal care for patients with advanced NSCLC. Areas where continued optimization is particularly emphasized include determining which type of sample(s) should be tested, which biomarkers should be analyzed in different patient subsets, and which assays are most appropriate for specific (sets of) markers, as well as logistical and administrative factors, such as turnaround times and cost/reimbursement considerations.1,5,6

As biomarker testing in NSCLC evolves, investigators continue to evaluate testing approaches with the goal of standardizing the process of oncogenic driver identification.

At the 2020 Molecular Analysis for Precision Oncology (MAP) Virtual Congress, held October 9 to 10, 2020, presentations focused on recent developments in molecular testing, including the results of studies comparing testing methods for aberrations in the MET and NTRK genes.

MET Exon 14 Skipping

Gain-of-function alterations in MET, which encodes a receptor tyrosine kinase, drive oncogenesis. One such alteration with important implications for NSCLC is MET exon 14 skipping, resulting from several types of mutation in either exon 14 itself, the adjacent introns, or the flanking splice sites. Regardless, the effect is the same: a critical ubiquitination site is lost, which leads to MET protein accumulation and activation, enhancing MET pathway signal transduction and culminating in tumorigenesis. Previously, immunohistochemistry was typically performed to detect MET overexpression due to copy number changes. However, next-generation sequencing (NGS) is now the preferred testing method because it can also identify MET exon 14 skipping mutations, the primary driver of oncogenesis.7

MET exon 14 skipping mutations are actionable because the resultant protein is responsive to MET inhibition using tyrosine kinase inhibitors (TKIs) such as capmatinib (Tabrecta),7 which was approved in May 2020 for use in adult patients with metastatic NSCLC harboring a MET exon 14 skipping mutation.3 Compared with their sensitivity to specific TKIs, this subset of patients has exhibited lower rates of response to immunotherapy despite frequent tumor expression of PD-L1,8 suggesting a dual predictive role for the MET exon 14 skipping mutation as a biomarker.

In a study presented at MAP 2020, tumor samples from patients with NSCLC and no other driver mutations were tested for MET exon 14 skipping mutations over a period of 14 months. The investigators compared 2 DNA-based methods: NGS on the Ion Proton platform using AmpliSeq technology and fragment analysis using polymerase chain reaction (PCR) and size-based electrophoretic separation of the amplicons for detection of large deletions.9

Of the 87 patient samples tested, 13 were determined to have a MET exon 14 skipping alteration, with 5 harboring splice variants and 8 carrying deletions affecting the splice site. Two of these deletions were large, spanning 41 and 66 base pairs; they were detected by fragment analysis but not NGS. Although NGS is widely considered superior to single-gene assays, these data indicate that it may have limitations in detecting specific alterations and that complementary methods or large-coverage intron screening could be an alternative for optimal detection of MET alterations to inform selection of first-line treatment, according to lead study author Romain Loyaux, from the Molecular Oncology Department of Georges-Pompidou European HospitalAPHP in Paris, France.

Commenting on the failure of the NGS assay to detect large MET exon 14 deletions, Loyaux stated that fragment analysis is a cheap and robust method to detect large deletions, especially when no RNA is available (FIGURE).9-11 He noted that anchored, multiplex, targeted RNA-based NGS, like the technology developed by the Archer company, may be a good alternative when RNA is available; however, it has a 20% failure rate.12

NTRK Fusion Detection

Fusions involving the NTRK genes, which encode a family of receptor tyrosine kinases, result in a constitutively activated chimeric protein that promotes oncogenesis and therefore, can be therapeutically targeted with TKIs.7 Two FDA-approved TKIs, entrectinib (Rozlytrek) and larotrectinib (Vitrakvi), have activity in NTRK fusionpositive solid tumors.13,14

Broad, hybrid-capture DNA-based NGS, with RNA-based anchored multiplex PCR as an adjunct, are currently the primary methods of detecting NTRK gene fusions in patients with lung cancer.7 The availability of entrectinib and larotrectinib will likely foster further development of NTRK fusion detection methods for use in routine clinical practice.

A recent study presented at MAP 2020 evaluated the analytical performancenamely, sensitivity, specificity, and precisionof 3 commonly available RNA-based NGS assays. The assays examined were TruSight Oncology 500 (TSO500) by Illumina, Oncomine Focus Assay (OFA) by Thermo Fisher Scientific, and Fusion- Plex Lung (AFL) by Archer.15

The limits of sensitivity and precision were assessed using droplet digital PCR with admixtures of both NTRK fusionpositive and negative samples, whereas specificity was evaluated using NTRK fusionnegative clinical samples. The data showed that all 3 NGS assays successfully detected NTRK fusions; however, technical differences between the assays may impact their performance. For instance, although all tested assays demonstrated strong specificity, the sample metrics were variable. Quality control (QC) success rates for OFA and TSO500 were 83% and 77%, respectively, but only 43% of samples on AFL passed all assay QC metrics. Notably, the different assays missed specific NTRK fusions; OFA failed to detect NTRK1-LMNA, NTRK1-TFG, and NTRK2- PAN3, and TSO500 failed to report NTRK3-ETV6 (E5N14) and NTRK3-ETV6 (E5N15).15

Clinical Utility of NGS Panels of Different Sizes

It has been established that multigene panels are superior to single-gene assays for biomarker testing in NSCLC2; however, data to inform clinicians selection of specific NGS gene panels have been lacking.

In a recent study presented at MAP 2020, a literature review was conducted to compare 2 commercially available DNA-based NGS gene panels: the Ion AmpliSeq Cancer Hotspot Panel, covering hotspots in 50 genes (Panel 50); and the FoundationOne panel, covering the complete exons of 315 genes (Panel 315). The clinical utility of each panel was determined based on the number of detectable actionable alterations in various solid tumor types that it contained. The data showed a substantial gain in actionability using the larger gene panel, which matched more actionable genetic mutations to FDA-approved or experimental drugs; the number of actionable alterations in various solid tumor types using Panel 315 was a median 50% higher compared with Panel 50 (t test, P <.001). The authors attributed this gain to the inclusion of more genes related to homologous recombination repair deficiency and microsatellite instability/immunotherapy response in the larger panel.16

In the current era of precision medicine in lung cancer, defined histological subtyping, oncogenic driver testing, and analysis of tumor PD-L1 expression/immunotherapy sensitivity are crucial steps prior to therapeutic decision-making in NSCLC. As additional targeted agents are investigated in clinical trials and the incidence of their molecular targets are characterized in patient populations, expanded molecular testing may become necessary.

Molecular pathologists will continue to play an integral role in the continuum of care in NSCLC, from diagnosis to clinical decision-making based on biomarker detection. Molecular testing is likely to expand rapidly, and additional molecular subtypes will be identified that help match more patients with the optimal targeted therapies, providing highly personalized treatment plans.

Details of analytical procedures and assays will continue to be refined.17 By combining defined sets of biomarkers with appropriate protocols for collecting NSCLC samples and optimized methods for assessing specific changes, clinicians will be able to actualize the promise of precision medicine for patients with this challenging malignancy.

References:

1. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321-346. doi:10.5858/arpa.2017-0388-CP

2. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 8.2020. Accessed October 26, 2020. https://bit.ly/2TKomAj

3. FDA grants accelerated approval to capmatinib for metastatic nonsmall cell lung cancer. FDA. May 6, 2020. Accessed November 2, 2020. https://bit.ly/360o7Xg

4. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA. June 16, 2020. Accessed November 2, 2020. https://bit.ly/2HWB64q

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10. Pruis MA, Geurts-Giele WRR, von der TJH, et al. Highly accurate DNAbased detection and treatment results of MET exon 14 skipping mutations in lung cancer. Lung Cancer. 2020;140:46-54. doi:10.1016/j.lungcan.2019.11.010

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12. Cohen D, Hondelink LM, Solleveld-Westerink N, et al. Optimizing mutation and fusion detection in NSCLC by sequential DNA and RNA sequencing. J Thorac Oncol. 2020;15(6):1000-1014. doi:10.1016/j.jtho.2020.01.019

13. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA. Published August 15, 2019. Accessed October 28, 2020. https://bit.ly/3mPhUEB

14. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. Published November 26, 2018. Accessed October 28, 2020. https://bit.ly/381dXZe

15. Bormann Chung C, Lee J, Barritault M, et al. Evaluating targeted next-generation sequencing (NGS) assays and reference materials for NTRK fusion detection. Ann Oncol. 2020;31(suppl 5):S1221. doi:10.1016/j.annonc.2020.08.2172

16. zdemir B, Charrier M, Gerard CL, et al. Comparison of the clinical utility of two different size next generation sequencing (NGS) gene panels for solid tumours. Ann Oncol. 2020;31(suppl 5):S1219. doi:10.1016/j.annonc.2020.08.2166

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Increased Attention on Testing for Oncogenic Drivers in NSCLC Advances the Promise of Precision Medicine - Targeted Oncology