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UofL-born company secures an additional $115 million to advance cell therapy – uoflnews.com

October 15th, 2020 8:58 pm

A company born at the University of Louisville has raised an additional $115 million to further develop a therapy that could improve the lives of kidney transplant recipients.

The company, Talaris Therapeutics Inc., plans to use the series B funding to support a Phase 3 clinical trial the last step before applying for FDA approval. This follows a $100 million series A funding round announced last year to hire staff and initiate the trial.

Talaris recently began dosing patients in that trial of the unique cell therapy, called FCR001, which allows living-donor kidney transplant recipients to stay off immunosuppression drugs they would otherwise need for the rest of their lives.

Immunosuppressants help prevent rejection of the transplanted organ, but can cause side effects, including high blood pressure, diabetes, high cholesterol, neurological effects, increased risk of infection and decline in kidney function over time.

This technology could help transplant patients live fuller, healthier lives,said UofL Executive Vice President for Research and Innovation, Kevin Gardner.This UofL research, in the hands of strong industry partners and backed by investors, is a big step in advancing our health.

FCR001 consists of stem cells taken from the organ donor and processed at the Talaris facility, then infused into the organ transplant recipient. The goal is to create a durable dual immune system (part donor-derived and part recipient) in the transplant recipient. These two immune systems coexist, recognizing both the recipients own body as well as the donated organ as self.

The new funding also will advance aplanned Phase 2 trial of FCR001 in diffuse systemic sclerosis, a severe form of the rare autoimmune disease scleroderma.

Talaris, formerly known as Regenerex LLC, was founded by UofL researcher and innovator Suzanne Ildstad to commercialize the pioneering work of her team at the university. She now serves as Talaris chief scientific officer.

This financing moves us one step closer to helping organ transplant recipients no longer be dependent on immunosuppressive drugs, resulting in a greatly improved quality of life, Ildstad said of the earlier Phase 3 trial financing. The support and research infrastructure at UofL have been invaluable in our journey to this important juncture.

In an earlier Phase 2 trial, FCR001 allowed 70% of living donor kidney transplant patients durably to be weaned off all of their immunosuppression treatments.

The Phase 3 trial is expected to enroll 120 adult living donor kidney transplant recipients at multiple sites across the U.S. To date, the trial has been initiated at five clinical sites around the country.

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Novellus Therapeutics Exclusively Licenses Induced Mesenchymal Stem Cells (iMSCs) to NoveCite for COVID-19 Related Acute Respiratory Distress Syndrome…

October 15th, 2020 8:58 pm

Novellus Therapeutics Exclusively Licenses Induced Mesenchymal Stem Cells (iMSCs) to NoveCite

"Novellus's iMSCs have the potential to be a breakthrough in the field of cellular therapy for acute respiratory conditions because of their high potency as demonstrated in our pre-clinical studies, as well as our ability to cost-effectively provide high doses and repeat doses." said Myron Holubiak, CEO of Citius.

"We are excited to be developing iMSCs because of their promise to save lives and reduce long term sequelae in patients with devastating respiratory diseases such as ARDS caused by COVID-19," said Matt Angel, Chief Science Officer of Novellus. He continued, "Our iMSCs have multimodal immunomodulatory mechanisms of action that make them promising for treatment of acute respiratory diseases."

About Novellus Therapeutics LimitedNovellus is a pre-clinical stage biotechnology company developing engineered cellular medicines using its patented non-immunogenic mRNA, high-specificity gene editing, mutation-free & footprint-free cell reprogramming and serum-insensitive mRNA lipid delivery technologies. Novellus is privately held and is headquartered in Cambridge, MA. For more information, please visit http://www.novellustx.com.

About NoveCite, Inc.NoveCite, Inc. is a newly formed subsidiary of Citius Pharmaceuticals, a late-stage specialty pharmaceutical company dedicated to the development and commercialization of critical care products, with a focus on anti-infectives and cancer care. For more information, please visit http://www.citiuspharma.com.

Contact: [emailprotected]

SOURCE Novellus Therapeutics

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Bone Therapeutics’ allogeneic cell therapy product, ALLOB, shows 90% fusion rate at 24 months in Phase IIa study in lumbar spinal fusion -…

October 15th, 2020 8:58 pm

Gosselies, Belgium, 14 October 2020, 7am CEST BONE THERAPEUTICS(Euronext Brussels and Paris: BOTHE), the cell therapy company addressing unmet medical needs in orthopedics and other diseases, today announces positive 24-month follow-up results for the Phase IIa study with the allogeneic cell therapy product, ALLOB, in patients undergoing lumbar spinal fusion procedures.

The 24-month data show a high percentage of successful lumbar vertebrae fusion of 90%. Patients also continue to experience important clinical improvements in function and pain, from as early as six months after treatment, up to the 24-month follow-up period.

Degenerative spine disorders have a major impact on the quality of life of patients. These impacts include decreases in the stability of the spine and pain in motion,said Dr. Alphonse Lubansu, M.D., Head of the Spinal Clinic, Erasme University Hospital, Universit libre de Bruxelles. The 24 month follow-up data of this Phase IIa clinical trial have demonstrated that patients treated with ALLOB in spinal fusion procedure show a high incidence in fusion, and benefit from a sustained, clinically meaningful improvement in function and pain throughout the 24 months following treatment together with a good safety profile. These results show that ALLOB in combination with the standard spine fusion surgery could be a promising treatment option to address the currently unmet needs of these patients.

This positive data forlumbar spinal fusion complementsthe strong Phase I/IIa results from ALLOB in patients with delayed union fractures,said Miguel Forte, MD, PhD, Chief Executive Officer of Bone Therapeutics. These studies provide promising clinical evidence for the potential ofBone Therapeuticsunique allogeneic cell therapy platform to address high unmet medical needs in orthopaedics and bone related disorders. We will now hold discussions with global regulators and our partners to explore a variety of options for the next stages of clinical development for ALLOB in different orthopedic indications, while pursuing the phase IIb study of ALLOB in difficult tibial fractures.In addition, theclinical results provide further evidence for the expansion of ALLOB and our platform of differentiated MSCs to other indications.

The multi-center, open-label proof-of-concept Phase IIa study was designed to evaluate the safety and efficacy of ALLOB administered, procedure in which an interbody cage with bioceramic granules mixed with ALLOB is implanted into the spine to achieve fusion of the lumbar vertebrae. The main endpoints of the 24-month follow-up analysis included safety and radiological assessments to evaluate vertebrae fusion (continuous bone bridges) and clinical assessments to evaluate improvement in patients functional disability as well as reduction in back and leg pain. The study evaluated 30 patients treated with ALLOB, 29 patients attended the 24-month visit.

Radiological data was collected from CT-scans at 24 months and assessed by three external readers. It showed a successful fusion of the lumbar vertebrae in 27 out of 30 patients (90%). In addition, the remaining 3 patients showed radiological evidence of bone formation. Treatment with ALLOB also resulted in a clear and statistically significant clinical improvement in function and reduction in pain over the 24-month follow-up period. Functional disability improved from the pre-treatment baseline to 24-month by a mean score of 60% (p<0.001) on the Oswestry Disability Index(1). Back and leg pain were strongly reduced by 57 to 62% (p<0.001) and 68 to 70% (p<0.001) respectively compared to pre-treatment baseline. Treatment with ALLOB was generally well-tolerated by the patients, consistent with previous reported results.

(1)The Oswestry Disability Index (ODI) is an index derived from the Oswestry Low Back Pain Questionnaire used by clinicians and researchers to measure a patients permanent functional disability. This validated questionnaire was first published by Jeremy Fairbank et al. in Physiotherapy in 1980. ODI score of 0%-20%: minimal disability; 21%-40%: moderate disability; 41%-60%: severe disability; 61%-80%: crippled; 81%-100%: bed bound.

About Spinal Fusion

Due to ageing populations and sedentary lifestyles, the number of people suffering from degenerative spine disorders continues to increase. Today, spinal fusion procedures are performed to relieve pain and improve patient daily functioning in a broad spectrum of degenerative spine disorders. Spinal fusion consists of bridging two or more vertebrae with the use of a cage and graft material, traditionally autologous bone graft or demineralised bone matrix placed into the intervertebral space for fusing an unstable portion of the spine and immobilizing a painful intervertebral motion segment. Over 1,000,000 spinal fusion procedures are performed annually in the US and EU, of which half at lumbar level and the market is growing at a rate of 5% per year. Although spinal fusion surgery is routine, non-fusion, slow progression to fusion and failure to eliminate pain are still frequent with up to 35% of patients not being satisfied with their surgery.

About ALLOB

ALLOB is the Companys off-the-shelf allogeneic cell therapy platform consisting of human allogeneic bone-forming cells derived from cultured bone marrow mesenchymal stem cells (MSC) from healthy adult donors, offering numerous advantages in product quality, injectable quantity, production, logistics and cost as compared to an autologous approach. To address critical factors for the development and commercialisation of cell therapy products, Bone Therapeutics has established a proprietary, optimised production process that improves consistency, scalability, cost effectiveness and ease of use of ALLOB. This optimized production process significantly increases the production yield, generating 100,000 of doses of ALLOB per bone marrow donation. Additionally, the final ALLOB product will be cryopreserved, enabling easy shipment and the capability to be stored in a frozen form at the hospital level. The process will therefore substantially reduce overall production costs, simplify supply chain logistics, improve patient accessibility and facilitate global commercialisation. The Company will implement the optimized production process for all future clinical trials with ALLOB.

About Bone Therapeutics

Bone Therapeutics is a leading biotech company focused on the development of innovative products to address high unmet needs in orthopedics and other diseases. The Company has a, diversified portfolio of cell and biologic therapies at different stages ranging from pre-clinical programs in immunomodulation to mid-to-late stage clinical development for orthopedic conditions, targeting markets with large unmet medical needs and limited innovation.

Bone Therapeutics is developing an off-the-shelf next-generation improved viscosupplement, JTA-004, which is currently in phase III development for the treatment of pain in knee osteoarthritis. Consisting of a unique combination of plasma proteins, hyaluronic acid a natural component of knee synovial fluid, and a fast-acting analgesic, JTA-004 intends to provide added lubrication and protection to the cartilage of the arthritic joint and to alleviate osteoarthritic pain and inflammation. Positive phase IIb efficacy results in patients with knee osteoarthritis showed a statistically significant improvement in pain relief compared to a leading viscosupplement.

Bone Therapeutics core technology is based on its cutting-edge allogeneic cell therapy platform with differentiated bone marrow sourced Mesenchymal Stromal Cells (MSCs) which can be stored at the point of use in the hospital. Currently in pre-clinical development, BT-20, the most recent product candidate from this technology, targets inflammatory conditions, while the leading investigational medicinal product, ALLOB, represents a unique, proprietary approach to bone regeneration, which turns undifferentiated stromal cells from healthy donors into bone-forming cells. These cells are produced via the Bone Therapeutics scalable manufacturing process. Following the CTA approval by regulatory authorities in Europe, the Company is ready to start the phase IIb clinical trial with ALLOB in patients with difficult tibial fractures, using its optimized production process. ALLOB continues to be evaluated for other orthopedic indications including spinal fusion, osteotomy, maxillofacial and dental.

Bone Therapeutics cell therapy products are manufactured to the highest GMP standards and are protected by a broad IP (Intellectual Property) portfolio covering ten patent families as well as knowhow. The Company is based in the BioPark in Gosselies, Belgium. Further information is available atwww.bonetherapeutics.com.

For further information, please contact:

Bone Therapeutics SAMiguel Forte, MD, PhD, Chief Executive OfficerJean-Luc Vandebroek, Chief Financial OfficerTel: +32 (0)71 12 10 00investorrelations@bonetherapeutics.com

For Belgian Media and Investor Enquiries:BepublicCatherine HaquenneTel: +32 (0)497 75 63 56catherine@bepublic.be

International Media Enquiries:Image Box CommunicationsNeil Hunter / Michelle BoxallTel: +44 (0)20 8943 4685neil.hunter@ibcomms.agency / michelle@ibcomms.agency

For French Media and Investor Enquiries:NewCap Investor Relations & Financial CommunicationsPierre Laurent, Louis-Victor Delouvrier and Arthur RouillTel: +33 (0)1 44 71 94 94bone@newcap.eu

For US Media and Investor Enquiries:LHA Investor RelationsYvonne BriggsTel: +1 310 691 7100ybriggs@lhai.com

Certain statements, beliefs and opinions in this press release are forward-looking, which reflect the Company or, as appropriate, the Company directors current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its subsidiary undertakings or any such persons officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release.

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Bone Therapeutics' allogeneic cell therapy product, ALLOB, shows 90% fusion rate at 24 months in Phase IIa study in lumbar spinal fusion -...

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Ronnie Coleman Starts Stem Cell Therapy to Help Recovery – generationiron.com

October 15th, 2020 8:58 pm

Injuries are a plague on the athlete. When we consider injuries at the professional level it can completely derail someones career. For those athletes who manage to battle through those injuries during their career, retirement can be quite painful. Just ask eight-time Olympia champion Ronnie Coleman.

Considered by many to be the greatest bodybuilder of all-time, Ronnie Coleman pushed his physique to the limit. Growing a massive amount of muscle throughout his career, Ronnie Coleman proved to be a genetic anomaly.

But while he may have dominated during his career, the injuries Coleman suffered during his career have been life altering.

Undergoing a number of surgeries since retirement, Coleman has experienced a tremendous amount of pain. His hips and back have given him the most issues. The eight-time champ detailed the injuries, specifically to his back and the numbness in his legs, that have caused him issues.

I got 14 screws, I got 2 cages and 2 rods. Circulation is kind of hard when you got all that hardware in your back.

With such trying injuries, Ronnie Coleman has come to welcome the idea of undergoing a different kind of treatment. Coleman has recently discussed the idea of undergoing stem cell therapy.

Looking to return to form, Ronnie Coleman discussed in a recent video about how hes ready to start stem cell therapy. Coleman discussed potentially undergoing the therapy when he appeared on the Joe Rogan Podcast.

Heres hoping that the therapy will be enough to help Ronnie Coleman fully recover. See the full interview here.

For more news and updates, follow Generation Iron on Facebook, Twitter, and Instagram.

Managing Editor at Generation Iron, Jonathan Salmon is a writer, martial arts instructor, and geek culture enthusiast. Check out his YouTube, Instagram, Twitter, Facebook, and Sound Cloud for in-depth MMA analysis.

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Comprehensive Analysis on Stem Cell Therapy Market based on types and application – AlgosOnline

October 15th, 2020 8:58 pm

The ' Stem Cell Therapy market' study Added by Market Study Report, LLC, provides an in-depth analysis pertaining to potential drivers fueling this industry. The study also encompasses valuable insights about profitability prospects, market size, growth dynamics, and revenue estimation of the business vertical. The study further draws attention to the competitive backdrop of renowned market contenders including their product offerings and business strategies.

The Stem Cell Therapy market research report offers significant information related to the key growth drivers, challenges & limitations, and various opportunities that will define the business scenario in the upcoming years.

Request a sample Report of Stem Cell Therapy Market at:https://www.marketstudyreport.com/request-a-sample/2422751?utm_source=Algosonline.com&utm_medium=AN

According to the research analysis, the Stem Cell Therapy market is estimated to generate commendable returns and showcase a y-o-y growth rate of XX% over the period of 2020-20205.

The advent of COVID-19 pandemic has compelled various businesses to re-establish their respective profit trajectory for the forthcoming years. The study offers a comprehensive assessment of the impact of coronavirus outbreak on the growth of Stem Cell Therapy market.

The document also analyzes the several segmentations and their impact on the growth of this market.

Major highlights from the Stem Cell Therapy market report:

Ask for Discount on Stem Cell Therapy Market Report at:https://www.marketstudyreport.com/check-for-discount/2422751?utm_source=Algosonline.com&utm_medium=AN

Stem Cell Therapy Market segments covered in the research report:

Regional segmentation: North America, Europe, Asia-Pacific, South America, Middle East and Africa

Product types: Autologous and Allogeneic

Applications spectrum: Musculoskeletal Disorder, Wounds & Injuries, Cornea, Cardiovascular Diseases and Others

Competitive outlook: Osiris Therapeutics, Molmed, JCR Pharmaceutical, NuVasive, Anterogen, Chiesi Pharmaceuticals, Medi-post, Pharmicell and Takeda (TiGenix

The key questions answered in the report:

For More Details On this Report: https://www.marketstudyreport.com/reports/global-stem-cell-therapy-market-2020-by-company-regions-type-and-application-forecast-to-2025

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Found: genes that sway the course of the coronavirus – Science Magazine

October 15th, 2020 8:57 pm

A study of some of the sickest COVID-19 patients, such as those placed on ventilators, has identified gene variants that put people at greater risk of severe disease.

By Jocelyn KaiserOct. 13, 2020 , 1:25 PM

Sciences COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

Its one of the pandemics puzzles: Most people infected by SARS-CoV-2 never feel sick, whereas others develop serious symptoms or even end up in an intensive care unit clinging to life. Age and preexisting conditions, such as obesity, account for much of the disparity. But geneticists have raced to see whether a persons DNA also explains why some get hit hard by the coronavirus, and they have uncovered tantalizing leads.

Now, a U.K. group studying more than 2200 COVID-19 patients has pinned down common gene variants that are linked to the most severe cases of the disease, and that point to existing drugs that could be repurposed to help. Its really exciting. Each one provides a potential target for treatment, says genetic epidemiologist Priya Duggal of Johns Hopkins University.

In a standard approach to finding genes that influence a condition, geneticists scan the DNA of large numbers of people for millions of marker sequences, looking for associations between specific markers and cases of the disease. In June, one such genomewide association study in The New England Journal of Medicine (NEJM) found two hits linked to respiratory failure in 1600 Italian and Spanish COVID-19 patients: a marker within the ABO gene, which determines a persons blood type, and a stretch of chromosome 3 that holds a half-dozen genes. Those two links have also emerged in other groups data, including some from the DNA testing company 23andMe.

The new study confirmed the chromosome 3 regions involvement. And because 74% of its patients were so sick that they needed invasive ventilation, it had the statistical strength to reveal other markers, elsewhere in the genome, linked to severe COVID-19. One find is a gene called IFNAR2 that codes for a cell receptor for interferon, a powerful molecular messenger that rallies the immune defenses when a virus invades a cell. A variant of IFNAR2 found in one in four Europeans raised the risk of severe COVID-19 by 30%. Baillie says the IFNAR2 hit is entirely complementary to a finding reported in Science last month: very rare mutations that disable IFNAR2 and seven other interferon genes may explain about 4% of severeCOVID-19 cases. Both studies raise hopes for ongoing trials of interferons as a COVID-19 treatment.

A more surprising hit from the U.K. study points to OAS genes, which code for proteins that activate an enzyme that breaks down viral RNA. A change in one of those genes might impair this activation, allowing the virus to flourish. The U.K. data suggest there is a variant as common and influential on COVID-19 as the interferon genetic risk factor.

Other genes identified by Baillies team could ramp up the inflammatory responses to lung damage triggered by SARS-CoV-2, reactions that can be lethal to some patients. One, DPP9, codes for an enzyme known to be involved in lung disease; another, TYK2, encodes a signaling protein involved in inflammation. Drugs that target those two genes proteins are already in useinhibitors of DPP9s enzyme for diabetes and baricitinib, which blocks TYK2s product, for arthritis. Baricitinib is in early clinical testing for COVID-19, and the new data could push it up the priority list, Baillie says.

The chromosome 3 region still stands out as the most powerful genetic actor: A single copy of the disease-associated variant more than doubles an infected persons odds of developing severe COVID-19. Evolutionary biologists reported last month in Nature that this suspicious region actually came from Neanderthals, through interbreeding with our species tens of thousands of years ago. It is now found in about 16% of Europeans and 50% of South Asians.

But the specific chromosome 3 gene or genes at play remain elusive. By analyzing gene activity data from normal lung tissue of people with and without the variant, the U.K. team homed in on CCR2, a gene that encodes a receptor for cytokine proteins that play a role in inflammation. But other data discussed at last weeks meeting point to SLC6Z20, which codes for a protein that interacts with the main cell receptor used by SARS-CoV-2 to enter cells. I dont think anyone at this point has a clear understanding of what are the underlying genes for the chromosome 3 link, says Andrea Ganna of the University of Helsinki, who co-leads the COVID-19 Host Genetics Initiative.

The U.K. genetics study did not confirm that the ABO variants affect the odds of severe disease. Some studies looking directly at blood type, not genetic markers, have reported that type O blood protects against COVID-19, whereas A blood makes a person more vulnerable. It may be that blood type influences whether a person gets infected, but not how sick they get, says Stanford University geneticist Manuel Rivas. In any case, O blood offers at best modest protection. There are a lot of people with O blood that have died of the disease. It doesnt really help you, says geneticist Andre Franke of the Christian-Albrecht University of Kiel, a coleader of the NEJM study.

Researchers expect to pin down more COVID-19 risk genesalready, after folding in the U.K. data plumbed by Baillies team, the COVID-19 Host Genetics Initiative has found another hit, a gene called FOXP4 implicated in lung cancer. And in a new medRxiv preprint posted last week, the company Ancestry.com reports that a gene previously connected to the effects of the flu may also boost COVID-19 susceptibility only in men, who are more likely to die of the disease than women.

Geneticists have had little luck so far identifying gene variants that explain why COVID-19 has hit Black people in the United States and United Kingdom particularly hard. The chromosome 3 variant is absent in most people of African ancestry. Researchers suspect that socioeconomic factors and preexisting conditions may better explain the increased risks. But several projects, including Baillies, are recruiting more people of non-European backgrounds to bolster their power to find COVID-19 gene links. And in an abstract for an online talk later this month at the American Society of Human Genetics annual meeting, the company Regeneron reports it has found a genome region that may raise the risk of severe disease mainly in people of African ancestry.

Even as more genetic risk factors are identified, their overall effect on infected people will be modest compared with other COVID-19 factors, Duggal says. But studies like the U.K. teams could help reveal the underlying biology of the disease and inspire better treatments. I dont think genetics will lead us out of this. I think genetics may give us new opportunities, Duggal says.

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Found: genes that sway the course of the coronavirus - Science Magazine

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Genetics of Height and Risk of Atrial Fibrillation: A Mendelian Randomization Study – DocWire News

October 15th, 2020 8:57 pm

Background

Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation.

In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 10-42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55-72; 38% female; recruitment 2008-2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations.

In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.

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A new way of predicting which kids will succeed in school: Look at their genes – NBC News

October 15th, 2020 8:57 pm

This article about the polygenic score was produced in partnership with The Hechinger Report, a nonprofit, independent news organization focused on inequality and innovation in education. This is part 3 of the series Gifted Educations Race Problem.

Many factors boost a child's chance of success in school like having wealthy parents who can afford tutors. But recent research has raised another possibility one that is discomforting to many the idea that scientists might someday be able to spot the genetic markers associated with academic performance.

To do this, researchers are turning to a relatively new genetic approach called the polygenic score, which assesses a persons likelihood for a specific future based on a combination of genetic variables. Its a research technique that some scientists are using to assess obesity or cancer risk, for instance. Now, researchers are exploring this approach in non-medical contexts, like academic or athletic success.

The scientists studying genetic markers in education are trying to untangle how nature and nurture together explain school performance. In principle, genetic screening might enable teachers to tailor their approach to groups of students. Educators might then more effectively instruct kids together in one classroom, rather than separating students into accelerated and low-level courses, which can deprive Black and brown children and children from low-income families of academic opportunities.

But some researchers fear this gene screening work could be misapplied and used to further racist or eugenic thinking, even though race is a social, not a genetic, classification. Theres an ugly history of proponents of eugenics, who believe in reshaping humanity by breeding superior traits and removing inferior traits, justifying their thinking with genetics. And there are debunked racist theories that have endeavored to falsely connect race and intelligence.

For now, the science is almost entirely based on data collected from people with European ancestry, which limits the conclusions that can be drawn from it, so researchers feel that theyve at least temporarily sidestepped the issue.

But that doesnt mean they arent worried about it and about the other ways this research could exacerbate inequities in education. Screening is expensive, for instance, increasing the odds that privileged students will qualify for extra enrichment or support before their less privileged peers.

Indeed, the idea of predicting students academic performance based on their genes comes with such a raft of ethical questions and unknowns that scientists in the field are urging caution. Polygenic scores are a potentially useful new scientific tool. At the same time, there are clear reasons to be concerned, Stanford University social scientist Ben Domingue said. Were going to have the capacity, with a vial of spit, to be able to predict all these different things.

Scientists and ethicists are also concerned about commercializing this work while the research is still evolving. Already, several companies sell reports to consumers that incorporate polygenic scores for health or various physical characteristics despite the fact that the scores are not perfect forecasters of a persons future.

Researchers in the field want to see more critical discussion of how their work could be applied in educational settings. If we dont pay attention now, systems will be created, constructed around us, responding to our genetic difference, said Sophie von Stumm, a psychologist at the University of York, in the United Kingdom, who studies genetics and education. Its high time to have this discussion. Honestly, were late to the party.

Related: College graduation may be partly determined by your genes, genome study of siblings finds

The polygenic score that could help predict academic performance aims to assess genetic markers related to educational attainment. In other words, it combines hundreds of common genetic variants that are linked to the number of years a person stays in school. In 2016, this score could explain about 5 percent of the variation in the level of education completed.

In 2018, researchers studied data from more than a million people across countries and found they could strengthen the polygenic score to explain 11 percent of the variation in educational attainment. That value puts the score on par with factors like a mothers level of education attainment, which explains 15 percent of variation, and household income, which explains about 7 percent.

There are genes that affect educational attainment that is for certain now, said Aysu Okbay, an economist at Vrije Universiteit in the Netherlands who contributed to the 2016 and 2018 studies.

The scores ability to explain variation in years of schooling could improve with more data. Rough estimates indicate about 80 percent of the variation in educational attainment comes from environmental factors the rest is genetic. With enough data, some scientists believe, the polygenic score could get close to explaining 20 percent of the difference in peoples level of education.

If so, the score would be an incredibly powerful single factor for making predictions about an individuals academic future even though the combined environmental variables still eclipse the role of genes. Its really not a puny predictor at this point, Domingue said.

In February, Domingue and his colleagues found that the polygenic score could help identify which groups of high schoolers had been placed into advanced math classes. The score could also point to students most likely to stick with advanced math courses across all four years of high school.

But polygenic scores also come laced with caveats. So many, in fact, that Okbay and her colleagues published a massive list of public FAQs including how the study was designed and whether the research could lead to stigmatization of people with certain genes to help readers interpret their research.

For more of NBC News' in-depth reporting, download the NBC News app

Paige Harden, a clinical psychologist at the University of Texas at Austin and a co-author on the math study likens the polygenic score to a credit score. Neither the polygenic nor the credit score can really forecast what will happen to a particular person. Instead, they provide a rough sense of how people with that score will, on average, fare. The score is better at gauging a groups overall performance than an individuals performance.

Harden and others acknowledge that its still a mystery how the genetic variants behind the score contribute to how far a person gets in school. We dont know what the mechanisms are, Okbay said. We dont know whether its causal or not.

Some research suggests the genes associated with education are related to the nervous system and the brain, raising the possibility that theyre connected to cognitive functions things like strong memory, creativity and perseverance that serve people well in school.

But the relationship could be nuanced. Domingue pointed out that there could be genetic factors that make a person more likely to be a supportive parent, which, in turn, would correlate to better school performance in their children. Because the child and parent share DNA, the polygenic score could capture gene variants in the child that explain educational performance but actually reflect the parents behavior.

There is also an enormous shortcoming in the datasets used for this research: Virtually all are built with DNA from people of European ancestry. Although there are biobanks in the works in Asia and Africa that could address this omission, for the time being, the scores are essentially only applicable to people of European descent. Youre basically developing a tool thats only useful for one segment of the population, Harden said.

Related: Gifted classes may not help talented students move ahead faster

Given all of these limitations, most scientists believe it would be unlikely, and inappropriate, for educators to use polygenic scores to determine student placement in specific classes or schools. Will someone be mad enough to track or stream on the basis of genetic predispositions? von Stumm said. Fortunately, I think were far from that.

There could be other ways of using this genetic information. Once genetic variants are better understood and enough data is in hand, for example, it might be possible to identify children with a predisposition to learning disabilities and intervene early. In May, von Stumm and her colleagues published a paper exploring whether a toddlers polygenic score for educational attainment could identify children at risk for language or literacy delays later in life. The conclusion: Were not there yet.

Critics caution that there is too much to establish ethically and scientifically before we confront those scenarios. Someday well understand the genetic contribution to educational success or to life success but it will be our grandchildren who understand it. It wont be us, bioethicist Arthur Caplan at NYU Langone Health said.

And even if we understood this information, its not clear how to best use the scores in schools. Last year, Stanfords Domingue and two colleagues wrote about a hypothetical case study: What happens when a parent tries to use genetic data, like a polygenic score, to make the case that their child deserves additional classroom support?

I dont know that I have good answers to that, he said. But the scenario hints at another serious concern: inequality. Not everyone will be able to afford genetic screening, even when there are meaningful scores for people across ancestries.

Still, researchers are already using the polygenic score to explore long-standing conundrums like why children with very similar advantages follow different trajectories in life.

We are all subject to a big genetic lottery that corresponds to an environmental lottery, von Stumm said. She added that research into the links between genetics and academic attainment could push people to examine fairness in meritocratic societies, given that some people may carry genetic strengths that give them a slight but significant academic advantage, that, in turn, improves other aspects of their lives.

Measuring a persons genetic advantage (or disadvantage) also allows scientists to control for it in their studies. That is, they can better study factors that society can change, such as spending on special programs, compulsory education and school interventions, without having their results biased by a sample of students who are genetically advantaged or disadvantaged.

And researchers can use the polygenic score to assess whether a school has failed students with high potential or if an intervention helped retain children who were otherwise likely to drop out. In the math paper published in February, Domingue, Harden, and their colleagues found that some schools better supported high school students with low polygenic scores than others, ensuring those kids stayed in school.

Harden hopes to see the science applied in ways that emphasize social justice and provide resources to programs that need them: Thats how I think we should be using the polygenic scores if we use them at all.

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Genetic Variants Linked to Severe Covid-19 – Physician’s Weekly

October 15th, 2020 8:57 pm

Genome-wide association study identifies ABO blood protein

The identification of a gene cluster associated with progression to severe disease in patients with Covid-19 strengthens findings from earlier studies suggesting a prominent role for ABO blood group locus in disease severity.

In the genome-wide association study (GWAS) involving patients hospitalized with Covid-19 in Italy and Spain during the local peak of the pandemic, patients with blood group A had an increased risk for progression to severe disease, while patients with blood group O had a lesser risk for progression.

The strongest signal for severe disease, however, was the rs11385942 insertion-deletion GA or G variant at locus 3p21.31, according to researchers from the Severe Covid-19 GWAS Group.

Blood-group specific analysis showed a higher risk for severe disease among patients with blood group A and a lower risk with blood group O.

The groups findings, published Oct. 14 in the New England Journal of Medicine, were originally reported online in June.

In a newly published commentary, researcher Arthur Kaser, MD, of the University of Cambridge Institute of Therapeutic Immunology and Infectious Disease wrote that the genome-wide association study represents a major leap toward disentangling the molecular mechanisms that cause severe Covid-19.

Kaser was not involved with the study.

This genome association study will set directions for research, he wrote, adding that a focus on the immunologic synapse between T cells and antigen-presenting cells appears to be warranted in the search for therapies to address the hyperinflammatory state known as cytokine storm that occurs in some patients with severe Covid-19.

Researchers from the Severe Covid-19 GWAS Group pragmatically compared data from patients hospitalized with severe Covid-19 (defined as respiratory failure), with data from contemporarily recruited blood donors with mostly unknown SARS-CoV-2 status and from historically healthy controls from the same region.

Associations were identified between the risk of developing severe Covid-19 and a multigene locus at 3p21.31 and the ABO blood group locus at 9q34.2.

No association signal was shown for the human leukocyte antigen (HLA) region, which is a regulator of infection immunity and has been suggested as a potential driver of Covid-19 severity.

At locus 3p21.31, the association signal spanned 6 genes: SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1.

The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-groupspecific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20-1.75; P=1.48104) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53-0.79; P=1.06105), wrote Tom H. Karlsen of the University of Oslo, and colleagues from the Severe Covid-19 GWAS Group.

In his editorial, Kaser noted that among the 6 candidate genes at 3p21.31, LZTFL1 might be the most compelling, with the rs11385942 variant and all other fine-mapped association signals that exceeded genome-wide significance located within it.

LZTFL1 is widely expressed and encodes a protein involved in protein trafficking to primary cilia, which are microtubule-based subcellular organelles acting as antennas for extracellular signals, he wrote. In T lymphocytes, LZTFL1 participates in the immunologic synapse with antigen-presenting cells, such as dendritic cells (these cells prime T-lymphocyte responses).

Kaser noted that of the other 5 candidate genes, 4 (CCR9, FYCO1, CXCR6 and XCR1) have roles in T-cell and dendritic-cell function, while SLC6A20 is a transporter with intestinal expression regulated by the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2).

Earlier research has shown the Covid-19 hyperinflammatory response to resemble secondary hemophagocytic lymphohistiocytosis (HLH), which is a rare and often fatal hyperinflammatory response triggered by autoimmune disorders, certain cancers, and infections.

Kaser wrote that while secondary HLH remains poorly understood, Mendelian-inherited primary HLH points toward CD8+ T lymphocytes, natural killer cells and dendritic cells triggering a cytokine storm involving macrophages.

Other shared features between secondary HLH and severe Covid-19 are cytopenia, hyperferritinemia, disseminated intravascular coagulation, acute respiratory distress syndrome, multiple organ dysfunction, excessive expansion of T lymphocytes, and bone marrow histiocytic hyperplasia with hemophagocytosis with aggregates of interstitial CD8+ lymphocytes, he noted.

The Severe Covid-19 GWAS Group concluded that further exploration of the (study) findings both as to their usefulness in clinical risk profiling of patients with Covid-19 and toward a mechanistic understanding of the underlying pathophysiology, is warranted.

In his commentary, Kaser concluded that the clinical success of treating Covid-19 patients on mechanical ventilation with the corticosteroid dexamethasone provides strong evidence that death may be caused by a late hyperinflammatory phase.

A therapeutic agent that converts severe Covid-19 into a manageable, nonfatal infection would render this pandemic a lesser concern, he wrote.

Because it is impossible to predict mechanisms straight from genomic coordinates, experimental testing of the biology of implicated genetic risk pathways is a route, albeit a potentially challenging one, toward that goal.

Salynn Boyles, Contributing Writer, BreakingMED

Karlsen reported grants from Stein Erik Hagen (via Canica A/S) during the conduct of the study; personal fees from Gilead Sciences, personal fees from Novartis, personal fees from Engitix, and personal fees from Intercept outside the submitted work.

Kaser had no disclosures.

Cat ID: 497

Topic ID: 495,497,282,497,125,190,926,192,927,151,59,928,925,934

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An evolutionary jolt helped cattle to spread across Africa. Now genetics must make them more productive – The Conversation Africa

October 15th, 2020 8:57 pm

African cattle breeds are astonishingly diverse, and often quite beautiful. They range from the dark-red Ankole of southern Uganda, with their massive heat-dissipating horns, to the Boran which thrive in the dusty plains of northern Kenya, to Ethiopias sturdy Mursi cattle, with their prominent shoulder humps and hanging dewlaps. The Kuri that graze on the grasses of Lake Chad are adept swimmers; the Red Fulani can trudge vast distances along the margins of the Sahara; and the famously disease-resistant Sheko inhabit tsetse fly-infested forests of southwest Ethiopia.

All billion or so cattle today descend from ancient aurochs, an extinct species of wild cattle that once inhabited large swaths of Eurasia. These cattle were domesticated on at least two distinct occasions approximately 10,000 years ago during the Neolithic era: once in south Asia leading to the zebu or humped cattle and the other in the Middle East leading to the taurine or humpless cattle.

In Africa, the oldest archaeological evidence of domestic cattle dates back to between 6000 and 5000 BC in western Egypt. These taurine cattle, initially confined to the Saharan-Sahelian belt, eventually reached isolated pockets of land in West and East Africa.

Africas cattle today have adapted to the climate, forage conditions, diseases and pests prevalent in their habitat. The individuals best adapted to their environments were more likely to survive and reproduce. They were also more favoured by people. Over time this led to different breeds and species.

Today there are an estimated 800 million livestock keepers across the continent. Cattle provide nutritious, calorie-dense food, much-needed income, and nitrogen-rich manure for replenishing soils. There are few regions of Africa where cattle do not play a central role, both economically and culturally.

But it was not always this way. My colleagues and I from the International Livestock Research Institute (ILRI) recently published a paper detailing how African cattle acquired their adaptive capacities.

Sifting through the DNA of 16 indigenous African breeds, we discovered a thousand-year-old event in which the worlds two main subspecies of cattle namely taurine and zebus mixed. This allowed African cattle after spending thousands of years confined to certain regions in Africa to diversify and spread across the continent.

Our findings help to explain how African cattle spread throughout the continent. But since they were selected and bred for resilience, African cattle never became as productive, in terms of meat or milk, as breeds in more temperate climates. Our hope is that, by studying the history hidden in indigenous cattle genomes, we can help guide efforts to breed for productivity without losing the breeds native resilience and sustainability.

Our new genome sequencing work revealed that, about a thousand years ago, pastoralist herders in the Horn of Africa began breeding the Asian zebu cattle with local taurine breeds.

The zebu offered traits that allowed cattle to survive in hot, dry climates. The taurine traits provided cattle with the ability to endure humid climates, where vector-borne diseases that affect cattle, like trypanosomiasis (or sleeping sickness) are common.

This event, which we dubbed an evolutionary jolt, allowed African cattle after spending thousands of years confined to a shifting patchwork of sub-regions in Africa to spread across the continent and flourish into the breeds we see today.

But this resilience came at a cost. African cattle are often not as productive in terms of growth rates, meat or milk as their European and American cousins. Canadian Holsteins, for example, can deliver 30 litres of milk per day, several times what most African breeds are capable of. Traditional Ethiopian Boran, for example, produced only four to six litres of milk per day.

Today scientists at ILRI, in partnership with governmental institutions in Tanzania and Ethiopia, are again trying to deliver an evolutionary jolt to Africas cattle. This time, however, they want to speed up the evolutionary clock by identifying genetic markers that signal both adaptability and productivity. Screening embryos for these markers could help scientists replicate in the lab the slow work of evolution by favouring the traits that most benefit farmers.

Earlier efforts to improve cattle productivity on the continent focused on importing cattle breeds from elsewhere, without adequately recognising African breeds unique resilience. Nearly, all these attempts have failed or resulted in crossbreeds with both adaptability and productivity diluted.

This time, we are focusing on sustainable productivityproductivity that builds on rather than disregards the resilience of indigenous African breeds.

But while we have new tools and shortcuts which enables scientists to analyse vast swaths of genetic data and decide which breeds could work well together, there are some lessons we should still draw from the first evolutionary jolt.

The first is that we shouldnt be overly concerned about crossbreeding. Because of a sense of national pride and wanting to conserve indigenous African cattle breeds, there is at times a tendency on the part of some to treat them as iconic, untouchable manuscripts.

This ignores the long tradition of crossbreeding practised by African livestock farmers and pastoralists they were (and still are) constantly mixing and matching breeds to select the animals best suited to their needs.

Another lesson is that, as scientists experiment and cross-breed, it is vitally important to remember that the local breeds have adaptations not all of them immediately obvious (a tolerance for episodic drought, for example) that have enabled their success. It is important that we do not lose those adaptive traits in the randomness of crossbreeding.

This will take innovative crossbreeding programs that incorporate scientists, government ministries, private partners and farmers to ensure the conservation of genetic information across the long life cycle of cattle generations.

And finally, its essential to include the practical, accumulated experience of pastoralists in these processes.

David Aronson, Senior Communications Advisor with ILRI, contributed to the writing of this article

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Nurse advises Rotary of the benefits of genetic testing – El Dorado News-Times

October 15th, 2020 8:57 pm

The El Dorado Rotary Club hosted Tammy McKamie, a genetic certified nurse at the Christus St. Michael Health System in Texarkana, on Monday at their regular meeting, where she spoke about the health benefits of genetic testing.

McKamie, who has worked as a medical professional for nearly 40 years, is the only credentialed genetic certified nurse in Texas, and also serves patients from Arkansas. On Monday, she discussed her specialization in genetics and the role ones genes may play in determining whether they develop cancer during their lives.

While 90% of those who develop cancer do so because of environmental and lifestyle factors, such as smoking or being exposed to carcinogenic chemicals, McKamie said some people are at a heightened risk due to genetic factors.

Almost every person is born with 23 pairs of chromosomes, half of which are inherited from their biological mother and the other half of which are inherited from their biological father.

On each one of these chromosomes, there are thousands of genes. If I add up all the genes in this DNA, were going to have about 20,000 genes, and each one of those has a purpose, McKamie said.

Some of those genes purposes are to protect the individual from developing cancer, she said, a medical breakthrough that was discovered in 1994 during research for the Human Genome Project.

God gave us genes to protect us from cancer, McKamie said. We have two of each gene that theyve discovered so far. One gene may protect you from multiple cancers, so if ones defective, you may be at risk for multiple cancers.

Rotarian Art Noyes asked whether genetic predisposition to cancer may have been related to actress Angelina Jolies decision to undergo a double mastectomy (breast removal) several years ago.

Yes, Angelinas mother had ovarian cancer, so she had this genetic testing years ago, McKamie said. She did the genetic testing and she had a genetic mutation in one of these genes. Angelina had never had cancer, but she had the genetic predisposition toward it.

In Jolies case, McKamie said, there was likely a mutation of the BRCA 1 or 2 gene, which can heighten ones susceptibility to several types of cancers, including breast cancer, ovarian cancer, prostate cancer, colorectal cancer and other types.

For those who opt not to undergo preventative surgeries, like Jolies mastectomy, knowing of any genetic defects can still help medical professionals that care for them, since they will be aware of their increased risk level. Those who do have a genetic predisposition to some types of cancer should undergo earlier and more frequent screenings so that any cancer that does develop can be treated sooner, McKamie said.

If you started out with this defect, we would not wait til 40 (years old) to do a mammogram we would start much earlier, she said. Everybody knows that if you detect cancer early, youre more likely to survive it.

McKamie said a defect in the BRCA 1 or 2 gene can heighten a womans risk of developing breast cancer significantly. For someone without a gene defect, the risk at 40 years old is about 0.5%; at 50 years old, about 2%; and at 70 years old, about 7%. For a woman who does carry a hereditary risk, the likelihood that they will develop breast cancer by age 40 increases to 10 to 20%, depending on which BRCA gene the defect is in; by age 50, the risk is 33 to 50%, and by 70 the risk is 58-87%, McKamie said. For men, the risk of breast cancer increases from 1% for the general population to 7% for those with a genetic defect.

People take it for granted that everythings working but if you knew that one of these was defective and you were at a higher risk for cancer, you might be more healthy, more conscious, McKamie said.

At Christus St. Michael, McKamie offers consultations for those who would like to undergo genetic testing to determine whether they might be at a heightened risk for developing cancer. First, she will take a detailed family medical history and explain to her patient how ones genes might increase their risk for cancer. Following that, she will draw one tube of blood from the patient and send it to a laboratory, with a typical turnaround time of two to three weeks, she said.

This testing is now even evolved to the point to where if you have cancer, the physicians will use it to determine the best type of drug to use to treat you, McKamie said. I get a lot of consults from our cancer physicians and oncologists because they need to know what type of drug to use to treat this person.

McKamie noted that Medicare pays 100% for this sort of genetic testing, and most other medical insurance companies follow their lead; additionally, should any out-of-pocket costs emerge once a patients sample reaches the testing lab, a representative from the lab will call the patient to ensure they still want the testing done.

Before a patient comes to Texarkana for a screening, McKamie will screen them over the phone to ensure they will qualify for coverage for the genetic testing, she said. Those who are interested in a consult can contact her at 903-614-2654 or [emailprotected]

[Cancer diagnostics and treatment] just really evolved, and it continues to evolve, McKamie said. This is the way of the future now.

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The 23andMe Genetic Kit Is an Insanely Cool Gift You May Just Want to Give Yourself – It’s on Sale For Prime Day! – Yahoo News

October 15th, 2020 8:57 pm

Amazon Prime Day is here, and have you seen these deals? They're bigger and better than ever, and we can't say we mind all that much. For two days only, you can score everything from fitness deals to beauty buys and kitchen gadgets. But, we'd be remiss if we didn't talk about the fact that it's October (seriously, how?) and gift-giving season is almost here. If you've got someone in your life who could use a cool present, consider this 23andMe Health + Ancestry Service ($99, originally $199).

This genetic-testing kit is beloved by millions, and will give you a unique and in depth look into your genetics. You can save $100 if you buy it today, which is major. Whether you want to check some people off your gifting list or are curious for yourself, now's the time to buy this insanely cool kit.

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Focusing on the Future of Genetic Testing in Oncology – OncLive

October 15th, 2020 8:57 pm

Germline genetic testing is essential in order to identify optimal treatments for patients with cancer, as well as detecting inherited mutations via cascade testing that could affect family members, according to John M.Carethers, MD, MACP, who emphasized that improvements to genetic testing technology and testing costs has increased not only the accuracy of, but access to these assays.

The technology in sequencing has moved from the old gels to capillary to ChIP [chromatin immunoprecipitation]-based, and has revolutionized the way we approached it. The depth of [genetic testing] coverage [has evolved], said Carethers. Sequencing technologies totally revolutionized this [process].

He added, There are some unusual situations in which additional technologies have to be used to figure out some of the ones that typical ChIP technologies don't fully explain. That has markedly changed the way we approach [testing] these days.

In an interview withOncLiveduring the 2020 Institutional Perspectives in Cancer (IPC) webinar on Precision Medicine, Carethers, a professor of Internal Medicine and Human Genetics at the University of Michigan, discussed recent developments in multi-gene panel testing.

OncLive: How are predictive and somatic genetic tests being utilized in clinical practice?

Carethers: In terms of germline testing, the benefit is knowing which disease you carry, and that information can also spread to other family members to understand whether they [are at an increased risk of getting a cancer diagnosis]. Sometimes, at least in my experience, [germline testing] does alleviate some anxiety. Some people get more anxious once they know they have a germline mutation, but in general, it does at least explain the reason why they're seeing certain diseases in the family. Thats the general benefit for germline testing.

The benefit of somatic testing is knowing the type of mutations that occur in the tumor; there may be a therapeutic drug or compound that is in current use that could benefit the patient. For instance, I had a patient with unresectable esophageal cancer. She was dying and her esophagus was almost completely obstructed with the tumor. She had a feeding tube put into her stomach and lost a lot of weight; she was literally counting out the days until she died. With some thought, we decided to take a sample of the tumor and do somatic testing.

She had some mutations that werent typically found in esophageal cancer, and we did have drugs [to treat her]. She was actually put on those drugs and the tumor shrunk dramatically to the point that she could eat again, she gained weight, and she lived another 5 years. Normally, she wouldn't have lasted more than a few months. The benefits of somatic testing is understanding the genetic makeup of the tumor in which you might be able to use some compounds that exist to benefit the patient. Thats the real goal of somatic testing.

There is an unusual situation for somatic testing, as well. For instance, in colon cancer, we know about Lynch syndrome, but there is also a Lynch-like syndrome. In Lynch-like syndrome, there is no germline [mutation], but the tumor has 2 somatic mutations of a mismatch repair deficient tumor. They can look like a Lynch syndrome tumor, and maybe even behave a little bit like a Lynch syndrome tumor, but they're really not caused by a germline mutation. Sometimes, somatic genetics can help us understand tumor genesis as well as ways to treat the tumor.

What changes have we seen recently in multigene panel testing? How are test results interpreted and how do they help guide treatment strategies?

There are patients who will walk in with the classic phenotype and then there are patients walking in who don't have the classic phenotype, yet they carry that mutation in the same gene. Multigene testing allows us to account for phenotypic variation.

Someone may walk in with colon cancer, the next person in the family might walk in with endometrial cancer, and the next person in the family may walk in with a skin tumor, but they all line up with the same mutation in Lynch syndrome. However, if you saw the skin tumor first, would you have thought of Lynch [syndrome]? [What about] if you saw the endometrium or the colon cancer? It depends on the specialty and the type of disease presentation they show up with. In many cases, though, the disease could be subtle.

For instance, there was a family I followed, which comprised the grandmother, mother, and daughter. The grandmother, who was well into her late 60s, had a Lynch syndrome mutation and got her colon removed appropriately. The mother was in her 40s with no cancers, but the daughter who was 21, developed colon cancer. It looked like it skipped a generation, yet, they all carry the same mutation. There's phenotypic variation, even with this exact same mutation in the family, because we're all genetically different to some, so there's probably modifiers and other things going on. However, if I can see that in this one family who I know [harbor that specific] mutation [then I know that] if multiple people walk into the clinic and have variations in their family histories and in their personal history of cancer, that we are seeing a wide phenotypic variation.

Now, instead of testing 1 gene at a time, we will test 30 or 50 genes at a time, and you can pick up some of these less penetrant genes that are causing the phenotypic variation. Sometimes there are major penetrant genes in these families.

What other barriers to germline testing need to be addressed?

We're always learning. Every year or so we add a few more genes to our repertoire and then, maybe they get on some of these panels. E3 ubiquitin ligase WWP1 is associated with PTEN hamartomatumorsyndrome, which is not on any panels, but the paper was published in the New England Journal of Medicine. We keep learning as we discover more and more of these genes. The more genes that we find tend to occur in less and less people, based on our current knowledge, but some of these patients present with these rare phenomena.

We're also finding out that some of these mutations arent specifically a change in the DNA sequencethere are methylation, or rearrangement, or even a deletion. You have to use other techniques in addition to sequencing to figure those families out or those families will be left in the lurch.

The downside of doing multigene panel testing is that now, if you push for more whole-exome and whole-genome sequencing, we have a lot more variants. One commercial lab got [results] back to me 2 months ago from a patient we had tested 4 years ago. They said, We finally have enough people [where we could determine that] his variant is not significant. It was good news. We are now more sure of variants because they now have more families in their database at the commercial lab. Sometimes it takes years to figure it out, unless we have functional analysis for all variants. Thats a big challenge right now.

Where do you hope to see the future of genetic testing head?

In a good way, genetic testing will probably [have a lower] cost and there [will be an] ease of doing it [with] whole-exome and whole-genome sequencing. It will even overtake panel testing over time because the machines are better and faster. The key, though, is having a database that you can go back and forth and analyze. Youre going to need the analytics and tools. What happens with the patient? Do I carry this [information] on a flash drive? Is it in a database I have to have access to?

It's not an easy answer and I'm not sure if the health system that a particular patient goes to is going to store all this information3 billion base pairs of informationand go back to it each time. Each place is going to have to have the right analytic tools to go back and [retrieve that information]. There are going to be some challenges with that, even though that's the way the technology is going.

The more challenging pieces [are related to] direct-to-consumer (DTC) testing. You don't always know what you're getting on those tests. We can test you for common diseases, such as diabetes and hypertension, but we also test you for BRCA1/2. In reality, very few of the DTC [tests] are doing sequencing or panel testing like we do clinically. Many of them are using single nucleotide polymorphisms (SNPs) that give you a suggestion. Many of these start from ancestry companies,and they recently moved into [testing for] these diseases because people are interested. I don't blame them for doing this, but the information they give might only [include] a fraction of the actual disease variants. If someone finds an SNP in BRCA1/2 or Lynch syndrome, you might need to see a doctor. [Based on your family history or phenotype,] we may have to send a ChIP test to verify [the results].

In some cases, people will test just to be curious, and they think they're going to have something, but there is zero evidenceno personal history and no family history. There are going to be some challenges with the DTC [testing] because we don't always know the type of test theyre getting and the information is not going to be as precise and could present challenges in the clinics. Some people are going to get upset because we're going to say, No, you don't need testing, or [patients will ask], Why does this test say I might have it but your test says I don't? We have to explain all this and those are going to be challenges.

What else would you like to add regarding the evolution of genetic testing?

There is phenotypic variability in the presentation of many of these syndromes. The standard now is multigenetic panel testing to try to assuage the phenotypic variation; we do pick up [genes in] people who we didn't necessarily think had that disease. I've been surprised too many times, so I'm not surprised anymore. A lot of these inherited conditions have phenotypic variability. If you have any suspicion or your primary care physician has any suspicion, feel free to send [a test] to our clinic because we can investigate that and do testing that's relatively cheap if there's a good cause to investigate that. It may save their life and the lives of their loved ones.

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Study will investigate the genetic impact of escaped farmed salmon – The Fish Site

October 15th, 2020 8:57 pm

The study has been launched in response to a recent escape of farm-raised salmon and will be managed by the wild-fish conservation body Fisheries Management Scotland, supported by scientists from Marine Scotland Science, and funded by Mowi Scotland.

The multi-year study of 115 sites aims to confirm wild salmons current genetic profile and to track for the potential of genetic changes should interbreeding of farmed and wild salmon occur.

In late August, Mowi Scotland confirmed that 48,834 farm-raised salmon escaped from its Carradale farm in the Firth of Clyde after it became detached from its seabed anchors during a combination of strong weather events.

Since the escape, Fisheries Management Scotland has been working with member District Salmon Fishery Boards and Fisheries Trusts, as well as angling associations, to monitor the situation and mitigate where possible. Escaped farmed salmon have been caught by anglers in multiple rivers across Loch Lomond, Ayrshire, Clyde, Argyll and in rivers in north-west England.

The priority for Fisheries Management Scotland and their members has been to ensure that any farmed fish are removed from the rivers, humanely dispatched, and scale samples submitted to enable accurate identification, and Mowi has committed to support these actions.

Dr Alan Wells, chief executive of Fisheries Management Scotland, said: We are very disappointed that this escape has occurred. The Carradale North farm is a new development, and we are all agreed it is not acceptable for such escapes to occur. It is crucial that lessons are learned, and that appropriate steps are taken to avoid such escapes happening in future.

We have welcomed Mowis commitment to work with us and to fund a comprehensive genetics study that will help us better understand the potential impacts. We will continue to engage with the industry and regulators, with a view to improving the situation for wild salmon and sea trout.

Ben Hadfield, COO of Mowi Scotland, said: I would like to thank Fisheries Management Scotland and their member District Salmon Fishery Boards and Fisheries Trusts for their efforts to remove these fish from rivers across the Firth of Clyde, and apologise for any disruption and concern this escape has caused all those with an interest in wild salmon. We have learned the root cause of the escape system anchor lines crossing and resulting in friction failure and acknowledge our responsibility to quickly learn from this event to prevent it from occurring again.

Polly Burns, aquaculture interactions manager at Fisheries Management Scotland, added: We would like to thank anglers for their continuing efforts to capture and report farmed fish entering our rivers. We have received about 150 reports of farmed fish captures from a range of rivers both within and out with the Firth of Clyde and we continue to urge anglers to report catches of farmed fish, using the reporting system on our website.

The Health and Welfare of Atlantic Salmon course

It is vital that fish farm operatives who are responsible for farmed fish are trained in their health andwelfare. This will help to ensure that fish are free from disease and suffering whilst at the same timepromote good productivity and comply with legislation.

This new and comprehensive study of genetic introgression aims to add to the understanding of one of the potential pressures on Scotlands wild salmon, which are approaching crisis-point. The Scottish Government has identified a range of high-level pressures on wild salmon to also include: over-exploitation, predation, invasive species, habitat loss and inshore commercial fisheries.

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Study will investigate the genetic impact of escaped farmed salmon - The Fish Site

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Making sense of genetic disease in dogs and cats – American Veterinary Medical Association

October 15th, 2020 8:56 pm

Understanding genetic disease in mixed-breed and purebred dogs and cats can bring about more effective treatments and better client service, says clinical geneticist and general practitioner Dr. Jerold Bell.

If we understand the genetic background of our patients, were better positioned to prevent, to mitigate, or to alter the expression of genetic disease, allowing our patients to be healthier in their lifetimes as well as to breed healthier dogs and cats, Dr. Bell said.

An adjunct professor at the Cummings School of Veterinary Medicine at Tufts University, Dr. Bell spoke about genetic diseases during the AVMA Virtual Convention 2020 this August. In addition to his teaching duties, Dr. Bell works as a solo practitioner, and he sees dogs and cats all day long and sees genetic disease in our patients all day long.

He explained that common genetic disorders are caused by ancient disease liability genes that preceded breed formation. Since these mutations occurred long before the separation of breeds, these diseases are seen across all breeds and in mixed breeds.

The most common hereditary diseases in dogs are allergies, followed by hip and elbow dysplasia; inherited cancers such as lymphoma, hemangiosarcoma, mast cell tumor, and osteosarcoma; patella luxation; nonstruvite bladder stones; hypothyroidism; mitral valve disease; inflammatory bowel disease; diabetes mellitus; retained testicles; and umbilical hernias.

In cats, the most prevalent genetic diseases are inflammatory cystitis, then feline urological syndrome, diabetes mellitus, lymphoplasmocytic gingivostomatitis, nonstruvite bladder stones, allergies, eosinophilic skin disease, and inflammatory bowel disease.

Disease is not a function of homozygosity, which happens when identical DNA sequences for a particular gene are inherited from both biological parents, nor is it a consequence of inbreeding. Rather, Dr. Bell explained, hereditary diseases are a result of the accumulation and propagation of specific disease liability genes. Breed-related deleterious genes accumulate in various ways, including direct selection for disease-associated phenotypes, linkage to selected traits, carriage by popular sires, genetic drift, andmost importantlythe absence of selection against deleterious phenotypes.

If we dont select for healthy parents to produce offspring, then we have no expectation of health in those offspring, Dr. Bell said. Not selecting for health is selecting for disease, and we need to understand that and pass that on to our breeder clients.

On the topic of disease and extreme phenotypes, Dr. Bell said brachycephalic obstructive airway syndrome is frequently diagnosed at veterinary clinics on account of the popularity of certain brachycephalic dog breeds, namely Pugs, French Bulldogs, and Bulldogs. Most breed standards do not call for the expression of extreme phenotypes, he said, nor do they select for the most extreme size or the most extreme brachycephalic trait.

Moderation away from extremes that cause disease should be the guiding principle in breeding, Dr. Bell noted, and in judging dog shows.

Common genetic diseases seen in mixed-breed dogs and cats occur randomly because of dispersed ancient liability genes, according to Dr. Bell. Uncommon and breed-specific recessive or complexly inherited disease is far less likely to occur in mixed-breed individuals.

Dr. Bell said designer-bred dogs and cats often have inherited diseases common in random-bred populations. They can also inherit disease liability genes shared by the parent breeds or parent species. So if youre breeding short-statured breeds together, it wouldnt be surprising to see patellar luxation, or in smaller toy size breeds, to see mitral valve disease, he said.

Hereditary disease manifests as a result of anatomical mismatch between parent breeds. We see a lot of this in dental disease, where we see crowding of teeth and malocclusions and misplaced teeth, Dr. Bell continued. Even in the musculoskeletal, if you breed two breeds with different body types together, we may see degenerative joint disease and poor joints. All of these things, all need to be monitored.

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Bionano Genomics’ Saphyr System Shown to be Indispensable for the Analysis of Certain Genetic Disease Causing Variants – GlobeNewswire

October 15th, 2020 8:56 pm

SAN DIEGO, Oct. 15, 2020 (GLOBE NEWSWIRE) -- Bionano Genomics, Inc. (Nasdaq: BNGO) announced that a study led by scientists and clinicians from the Institute for Human Genetics at the UCSF School of Medicine and the Department of Pediatrics at the University of Colorado School of Medicine and published in bioRxiv used Bionanos proprietary genome imaging technology to identify novel disease causing variants in patients with three different genetic diseases and in a diverse control dataset of 154 individuals. The study found that Bionano's Saphyr System was able to comprehensively analyze complex genome structures called segmental duplications and helped identify several novel structural variations associated with each disease causing locus increasing the understanding of these diseases.

Segmental duplications are large segments of repetitive sequences tens to hundreds of thousands of base pairs in size. Short-read and long-read sequencing technologies cannot span these large segments of the genome. Only Bionanos optical mapping technology can image single molecules that are so long that they span the segmental duplications. These repetitive sequences can interact with each other when sperm or eggs are created and their rearrangement can cause severe genetic disease. Some of the most common of such diseases are microdeletions at 7q11.23, also known as Williams-Beuren syndrome (WBS), 15q13.3 microdeletion syndrome, 16p12.2 microdeletion syndrome and 22q11.2 deletion syndrome, also known as DiGeorge syndrome.

This study, published in bioRxiv, provides a population-level analysis of segmental duplications in 154 people and in patients with WBS, 15q13.3, and 16p12.2 microdeletion syndromes. Several novel SVs were detected for each locus, and the exact disease causing rearrangement was determined with much higher accuracy than was formerly possible without Saphyr. As previously announced, a recent publication in the journal Nature published on July 22, 2020 also discussed the unique contribution of Bionanos optical mapping technology to understanding the genetic causes of DiGeorge syndrome.

Erik Holmlin, Ph.D., CEO of Bionano Genomics commented, The microdeletion and microduplication syndromes are common genetic disorders, yet the exact genomic structures that cause them have been difficult or impossible to characterize with current sequencing-based methods. Even though microdeletion syndromes are commonly represented by hallmark features, in many cases a wide variability in clinical features is observed. Being able to understand and measure the subtle structural differences in microdeletions among different patients could allow for better clinical or therapeutic management. An increasing number of studies have relied on Bionanos Saphyr system to characterize disease-causing structural variants that could not be correctly analyzed with other molecular techniques. We will continue to make our technology available to researchers everywhere who want to greatly expand the capabilities of their genomic analysis.

The publication is available at https://www.biorxiv.org/content/10.1101/2020.04.30.071449v1.full

About Bionano GenomicsBionano is a genome analysis company providing tools and services based on its Saphyr system to scientists and clinicians conducting genetic research and patient testing, and providing diagnostic testing for those with autism spectrum disorder (ASD) and other neurodevelopmental disabilities through its Lineagen business. Bionanos Saphyr system is a platform for ultra-sensitive and ultra-specific structural variation detection that enables researchers and clinicians to accelerate the search for new diagnostics and therapeutic targets and to streamline the study of changes in chromosomes, which is known as cytogenetics. The Saphyr system is comprised of an instrument, chip consumables, reagents and a suite of data analysis tools, and genome analysis services to provide access to data generated by the Saphyr system for researchers who prefer not to adopt the Saphyr system in their labs. Lineagen has been providing genetic testing services to families and their healthcare providers for over nine years and has performed over 65,000 tests for those with neurodevelopmental concerns. For more information, visitwww.bionanogenomics.com or http://www.lineagen.com.

Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as may, will, expect, plan, anticipate, estimate, intend and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) convey uncertainty of future events or outcomes and are intended to identify these forward-looking statements. Forward-looking statements include statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things: the contribution of Bionanos technology to the analysis or understandings of microdeletion syndromes and future development of better clinical or therapeutic management for such diseases; the effectiveness and utility of Bionanos technology in clinical settings; Saphyrs capabilities in comparison to other genome analysis technologies; the benefits of Bionanos optical mapping technology and its ability to facilitate genomic analysis in future studies; and Bionanos strategic plans. Each of these forward-looking statements involves risks and uncertainties. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the risks and uncertainties associated with: the impact of the COVID-19 pandemic on our business and the global economy; general market conditions; changes in the competitive landscape and the introduction of competitive products; changes in our strategic and commercial plans; our ability to obtain sufficient financing to fund our strategic plans and commercialization efforts; the ability of medical and research institutions to obtain funding to support adoption or continued use of our technologies; the loss of key members of management and our commercial team; and the risks and uncertainties associated withour business and financial condition in general, including the risks and uncertainties described in our filings with the Securities and Exchange Commission, including, without limitation, our Annual Report on Form 10-K for the year ended December 31, 2019 and in other filings subsequently made by us with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management's assumptions and estimates as of such date. We do not undertake any obligation to publicly update any forward-looking statements, whether as a result of the receipt of new information, the occurrence of future events or otherwise.

CONTACTSCompany Contact:Erik Holmlin, CEOBionano Genomics, Inc.+1 (858) 888-7610eholmlin@bionanogenomics.com

Investor Relations Contact:Ashley R. RobinsonLifeSci Advisors, LLC+1 (617) 430-7577arr@lifesciadvisors.com

Media Contact:Darren Opland, PhDLifeSci Communications+1 (617) 733-7668darren@lifescicomms.com

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Bionano Genomics' Saphyr System Shown to be Indispensable for the Analysis of Certain Genetic Disease Causing Variants - GlobeNewswire

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NeuBase Therapeutics Announces Addition of Peter Nielsen, Ph.D., Inventor of Peptide Nucleic Acid Technology, to Scientific Advisory Board – BioSpace

October 15th, 2020 8:56 pm

PITTSBURGH, Oct. 13, 2020 (GLOBE NEWSWIRE) -- NeuBase Therapeutics, Inc. (NASDAQ: NBSE) (NeuBase or the Company), a biotechnology company accelerating the genetic revolution using a new class of synthetic medicines, announced the addition of Peter Nielsen, Ph.D. to its scientific advisory board. Dr. Nielsen, the primary inventor of peptide nucleic acid (PNA) technology, brings extensive experience in genetic medicine to NeuBase as the Company optimizes its PATrOL therapies and moves them towards the clinic.

We are honored to welcome Dr. Nielsen, a transformational leader in the field of genetics and genomic technologies, to the NeuBase scientific advisory board. His unique perspective gained over his distinctive career will undoubtedly provide valuable insight and complement our team of renowned experts, said Dietrich A. Stephan, Ph.D., chief executive officer of NeuBase. We believe that our new class of synthetic medicines, which relies on the elegant scaffold chemistry invented by Dr. Nielsen, has the potential to change the treatment landscape for many diseases, both common and rare. We look forward to leveraging his unparalleled knowledge as we continue to advance our PATrOL platform under the guidance of our outstanding group of scientific advisors.

Dr. Nielsen added, NeuBases PNA technology is among the first to be advanced through development for therapeutic applications, and I am thrilled to be part of the revolution the Company is leading. I look forward to working with the team and lending my guidance as NeuBase progresses its first-in-class medicines.

Dr. Peter Nielsen is a leading expert in gene targeting, RNA interference and chemical replication and translation and was one of the inventors of PNAs in 1991. He is currently a professor at the University of Copenhagen where his lab focuses on PNAs in regard to drug discovery, gene targeting, antisense principles, cellular and in vivo delivery and administration of biopharmaceuticals. He is the co-author of more than 400 scientific papers and reviews as well as over 20 patents and patent applications, and he serves on the advisory board of four scientific journals.In addition to his esteemed academic career, Dr. Nielsen is the co-founder of two biotech companies in Denmark and is a member of EMBO and the Danish Academy of Technical Sciences. He received his Ph.D. in 1980 from University of Copenhagen.

About NeuBase Therapeutics, Inc.NeuBase is accelerating the genetic revolution using a new class of synthetic medicines. NeuBases designer PATrOL therapies are centered around its proprietary drug scaffold to address genetic diseases at the source by combining the highly targeted approach of traditional genetic therapies with the broad organ distribution capabilities of small molecules. With an initial focus on silencing disease-causing mutations in debilitating neurological, neuromuscular and oncologic disorders, NeuBase is committed to redefining medicine for the millions of patients with both common and rare conditions. To learn more, visit http://www.neubasetherapeutics.com.

Use of Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act. These forward-looking statements are distinguished by use of words such as "will," "would," "anticipate," "expect," "believe," "designed," "plan," or "intend," the negative of these terms, and similar references to future periods. These views involve risks and uncertainties that are difficult to predict and, accordingly, our actual results may differ materially from the results discussed in our forward-looking statements. Our forward-looking statements contained herein speak only as of the date of this press release. Factors or events that we cannot predict, including those risk factors contained in our filings with the U.S. Securities and Exchange Commission, may cause our actual results to differ from those expressed in forward-looking statements. The Company may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in the forward-looking statements, and you should not place undue reliance on these forward-looking statements. Because such statements deal with future events and are based on the Company's current expectations, they are subject to various risks and uncertainties, and actual results, performance or achievements of the Company could differ materially from those described in or implied by the statements in this press release, including: the Company's plans to develop and commercialize its product candidates; the timing of initiation of the Company's planned clinical trials; the timing of the availability of data from the Company's clinical trials; the timing of any planned investigational new drug application or new drug application; the Company's plans to research, develop and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of the Company's product candidates; the Company's commercialization, marketing and manufacturing capabilities and strategy; global health conditions, including the impact of COVID-19; the Company's ability to protect its intellectual property position; and the requirement for additional capital to continue to advance these product candidates, which may not be available on favorable terms or at all, as well as those risk factors contained in our filings with the U.S. Securities and Exchange Commission. Except as otherwise required by law, the Company disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date hereof, whether as a result of new information, future events or circumstances or otherwise.

NeuBase Investor Contact:Dan FerryManaging DirectorLifeSci Advisors, LLCDaniel@lifesciadvisors.comOP: (617) 430-7576

NeuBase Media Contact:Cait Williamson, Ph.D.LifeSci Communicationscait@lifescicomms.comOP: (646) 751-4366

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NeuBase Therapeutics Announces Addition of Peter Nielsen, Ph.D., Inventor of Peptide Nucleic Acid Technology, to Scientific Advisory Board - BioSpace

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Genetic Variant for EFIH in Thoroughbreds Found The Horse – TheHorse.com

October 15th, 2020 8:56 pm

Researchers at the University of California, Davis, School of Veterinary Medicine have identified a genetic cause for the fatal condition equine familial isolated hypoparathyroidism (EFIH) in Thoroughbreds, marking the first genetic variant for hypoparathyroidism identified in any domestic animal species. Additionally, this is the first widely available genetic test for Thoroughbreds.

The study, led by Carrie Finno, DVM, PhD, Dipl. ACVIM, and Gary Magdesian, DVM, CVA, Dipl. ACVIM, ACVECC, ACVCP, wasreportedin the journalPLoS Genetics.Genetic testingcan now be performed at theUC Davis Veterinary Genetics Laboratoryto identify horses with the variant and avoid mating carriers that could produce affected foals.

For Thoroughbred owners and breeders, the loss of a foal has tremendous economic and emotional impacts, said first author Victor Rivas, who conducted the project as part of his undergraduate training in Finnos laboratory. It is important to promote safe and strategic breeding habits by actively breeding horses genetically screened not only for EFIH but for other diseases that may impact quality of life.

Foals affected with EFIH suffer from low blood calcium concentrations, resulting in involuntary muscle contractions, muscle stiffness that leads to a stiff gait and can progress to an inability to stand, seizures, fevers, and an abnormally fast pulse. Parathyroid hormone is typically produced to increase calcium levels in the body, but in these foals concentrations are low or inappropriately normal (i.e., they should be high due to the low calcium). Affected foals die or are euthanized due to poor prognosis. Necropsy results reveal underdeveloped or absent parathyroid glands.

Previously termed idiopathic hypocalcemia, EFIH has been observed in Thoroughbred foals up to 35 days of age. Disease onset and progression are likely determined by the amount of calcium in the diet early in life. This can vary based on dam milk calcium concentration and the amount of milk ingested.

In the current study, the researchers determined an autosomal recessive mode of inheritance and performed whole genome sequencing of two affected foals. A mutation in therap guanine nucleotide exchange factor 5(RAPGEF5) gene was present in two copies (homozygous) in both foals. They further analyzed the variant in a frog developmental model and demonstrated loss of function of the RAPGEF5 protein leading to aberrant development. Based on these data, the researchers hypothesize thatRAPGEF5might play a role in the derivation of the parathyroid gland during development.

Researchers have not identified the variant in individuals from 12 other breeds. The allele frequency for theRAPGEF5variant in an expanded set of 82 randomly selected, unaffected Thoroughbreds was 0.018. An unbiased allele frequency study has not been performed, so the allele frequency in the larger Thoroughbred population is currently unknown.

The next steps are to assess the allele frequency in a large population of randomly selected Thoroughbreds, said Finno. Additionally, we have discussed collaborating with Dr. Nathan Slovis at Hagyard Equine Medical Institute in Kentucky to test for the variant in cases of sudden death in Thoroughbred foals.

The clinical presentation of EFIH is similar to human familial hypoparathyroidism. Because theRAPGEF5gene is highly conserved across species, it is a potential new candidate gene for primary hypoparathyroidism in humans, the researchers said.

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Genetic Variant for EFIH in Thoroughbreds Found The Horse - TheHorse.com

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Identifying Genetic Variants, Matching With Targeted Therapies Serve as Next Great Challenge With Germline Testing in Oncology – OncLive

October 15th, 2020 8:56 pm

The revolution of genetic testing has led to more accurate and widespread assays for patients with cancer; however, as more genetic variants are identified, it has become a greater challenge to determine the optimal treatment for an individual patient, according to GouthamNarla, MD, PhD.

As we sequence more genes, we will have more information, which is a good thing, said Narla. Of course, we will also find more variants that, at this time, we don't know whether they're pathogenic or benign. They get lumped into the uncertain category, which creates uncertainty for patients and for providers, as well.

In an interview withOncLiveduring the 2020 Institutional Perspectives in Cancer (IPC) webinar on Precision Medicine, Narla, an associate professor in the Department of Medicine; chief of the Division of Genetic Medicine, Department of Medicine; and associate director of the Medical Scientist Training Program, University of Michigan, further discussed the utility of genomic testing and updates in next generation sequencing (NGS).

OncLive: Could you discuss the key advances in cancer genetics? What are some of the mechanisms that have driven its development?

Narla: A couple of major advancements we've seen in cancer genetics is the identification of additional disease-causing variants. It used to be when I first trained as a medical geneticist, we really only knew about BRCA1/2 and some of the mismatch repair genes. Now, we know about other genes, including PALB2, and other members and genes in that family. That has expanded the testing opportunities for our patients.

The other aspect that has been very exciting is now some of these gene variants are predictive of response to therapies. We have therapies that can be specifically used and work for patients who harbor some of these germline variants. That has really changed the way in which we have treated patients who carry these variants.

What are some of the recent developments in NGS?

Previously, we were doing single-gene testing, oftentimes by Sanger sequencing. Now, we can do large panels of genes depending upon the company and the panel; these comprise anywhere from 60 to 70 genesin some cases, several thousand genes. It has allowed us to collect vast amounts of sequencing information. Some of it will not be directly actionable now, but it still fuels research opportunities for us at major academic medical centers, and when more knowledge [is] gained, we go back to some of those sequencing results to see if, in fact, there was something that is now actionable based upon new knowledge.

How are we using this information to develop targeting strategies?

A lot of the approaches that we are using now may not involve the directly targeting the defective gene or protein, but they are leveraging knowledge about how that defective gene or protein causes activation of targetable pathways. For example, when it comes to BRCA1 loss, that creates a unique opportunity to use a PARP inhibitor in a synthetic lethal interaction, where those cells become highly dependent upon that enzyme. Then, you can inhibit with small molecules [or perhaps] approved PARP inhibitors, such as olaparib (Lynparza), and others for which there are now [a number of approved drugs that can target] a range of BRCA-deficient metastatic tumors.

How else has genomic testing evolved?

The evolution has been both in the number of individuals that we test, as well as how many genes we test. [For example, we used to] test families in which there are numbers of individuals who have cancer and we had a strong pretest probability that they would have a germline variant. Now, in fact, every patient with metastatic ovarian cancer, regardless of family history, gets tested. This is because we have PARP inhibitors for them. It not only has implications for their family but it also has implications for their treatment choices.

What guidelines have been helpful to your practice as it relates to genomic testing?

There are a number of organizations from the American Cancer Society to National Cancer Institute and the National Comprehensive Cancer Network (NCCN) that have very robust guidelines on who to test. There is also a little bit of subjectivity in making an appraisal with a genetics professional, meaning a genetic counselor or a medical geneticist, because not every family will fit the structure or will even know the entirety of their family history. There is some nuance to this, but there are definitely very established guidelines that exist and that we use when making these types of decisions.

However, the NCCN guidelines are very good and are used by [our institution. Then we apply our own nuances when we see the patient on a case by case basis. But, [in terms of] informing who should be tested and who should not, and which individual in the family should be [tested], the NCCN guidelines are a very good [resource].

What challenges could be addressed with future research?

I would like to see more of an effort to share data across all institutions and testing companies to reclassify these variants. I would like to see more basic science and translational science around what we call variant reclassification, so that we can really make definitive calls about the sequence changes that we see. The more genes we sequence, the more variants we find, and on larger panels, [we can see these uncertain variants in up to] 20% of patients. We're finding something in a gene, but we don't know whether it's good or bad for the patient.

Are there any new capabilities or technologies emerging that you find particularly exciting?

From a technology perspective, the last 10 years in sequencing has been a revolution; the cost of sequencing has come down and the accuracy has gone up. I'm not sure that we're going to see that much more of a revolution in the sequencing technology; it will be more efficient and more cost effective. We're [going to see] the identification of new genes associated with disease [and will therefore] it will be in the variant reclassification space.

What testing or sequencing studies are of particular interest?

One type of study that has read-out recently comprise the effectiveness of immunotherapy in patients who have mismatch repair deficient tumors. That has been really game-changing for those patients. The other major study is the use of PARP inhibitors in BRCA-mutant tumorsoriginally in the second- and third-line settings of ovarian cancer. [PARP inhibitors] have now moved to maintenance [therapy], pancreatic cancer, prostate cancer, and others. That has changed the management of patients with BRCA-positive tumors.

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Identifying Genetic Variants, Matching With Targeted Therapies Serve as Next Great Challenge With Germline Testing in Oncology - OncLive

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Found: genes that sway the course of the coronavirus – Science

October 15th, 2020 8:56 pm

Science's COVID-19 coverage is supported by the Pulitzer Center.

It's one of the pandemic's puzzles: Most people infected by SARS-CoV-2 never feel sick, whereas others develop serious symptoms or even end up in an intensive care unit clinging to life. Age and preexisting conditions, such as obesity, account for much of the disparity. But geneticists have raced to see whether a person's DNA also explains why some get hit hard by the coronavirus, and they have uncovered tantalizing leads.

Now, a U.K. group studying more than 2200 COVID-19 patients has pinned down common gene variants that are linked to the most severe cases of the disease, and that point to existing drugs that could be repurposed to help. It's really exciting. Each one provides a potential target for treatment, says genetic epidemiologist Priya Duggal of Johns Hopkins University.

Kenneth Baillie of the University of Edinburgh, an intensive care physician and geneticist, led the new study, which he discussed on 2 October at an online meeting of a data-pooling effort called the COVID-19 Host Genetics Initiative. He's hoping the results, also posted as a preprint on medRxiv, will speed treatments, although he cautions that any clinical trial inspired by the findings should wait for the study's acceptance in a peer-reviewed journal. Because the epidemic is progressing at such an alarming rate, even a few months of time saved will save lots of lives, Baillie says.

A study of some of the sickest COVID-19 patients, such as those placed on ventilators, has identified gene variants that put people at greater risk of severe disease.

In a standard approach to finding genes that influence a condition, geneticists scan the DNA of large numbers of people for millions of marker sequences, looking for associations between specific markers and cases of the disease. In June, one such genome-wide association study in The New England Journal of Medicine (NEJM) found two hits linked to respiratory failure in 1600 Italian and Spanish COVID-19 patients: a marker within the ABO gene, which determines a person's blood type, and a stretch of chromosome 3 that holds a half-dozen genes. Those two links have also emerged in other groups' data, including some from the DNA testing company 23andMe.

The new study confirmed the chromosome 3 region's involvement. And because 74% of its patients were so sick that they needed invasive ventilation, it had the statistical strength to reveal other markers, elsewhere in the genome, linked to severe COVID-19. One find is a gene called IFNAR2 that codes for a cell receptor for interferon, a powerful molecular messenger that rallies the immune defenses when a virus invades a cell. A variant of IFNAR2 found in one in four Europeans raised the risk of severe COVID-19 by 30%. Baillie says the IFNAR2 hit is entirely complementary to a finding reported in Science last month: Very rare mutations that disable IFNAR2 and seven other interferon genes may explain about 4% of severe COVID-19 cases (25 September, p. 155). Both studies raise hopes for ongoing trials of interferons as a COVID-19 treatment.

A more surprising hit from the U.K. study points to OAS genes, which code for proteins that activate an enzyme that breaks down viral RNA. A change in one of those genes might impair this activation, allowing the virus to flourish. The U.K. data suggest there is a variant as common and influential on COVID-19 as the interferon genetic risk factor.

Other genes identified by Baillie's team could ramp up the inflammatory responses to lung damage triggered by SARS-CoV-2, reactions that can be lethal to some patients. One, DPP9, codes for an enzyme known to be involved in lung disease; another, TYK2, encodes a signaling protein involved in inflammation. Drugs that target those two genes' proteins are already in useinhibitors of DPP9's enzyme for diabetes and baricitinib, which blocks TYK2's product, for arthritis. Baricitinib is in early clinical testing for COVID-19, and the new data could push it up the priority list, Baillie says.

The chromosome 3 region still stands out as the most powerful genetic actor: A single copy of the disease-associated variant more than doubles an infected person's odds of developing severe COVID-19. Evolutionary biologists reported last month in Nature that this suspicious region actually came from Neanderthals, through interbreeding with our species tens of thousands of years ago. It is now found in about 16% of Europeans and 50% of South Asians.

But the specific chromosome 3 gene or genes at play remain elusive. By analyzing gene activity data from normal lung tissue of people with and without the variant, the U.K. team homed in on CCR2, a gene that encodes a receptor for cytokine proteins that play a role in inflammation. But other data discussed at last week's meeting point to SLC6Z20, which codes for a protein that interacts with the main cell receptor used by SARS-CoV-2 to enter cells. I don't think anyone at this point has a clear understanding of what are the underlying genes for the chromosome 3 link, says Andrea Ganna of the University of Helsinki, who co-leads the COVID-19 Host Genetics Initiative.

The U.K. genetics study did not confirm that the ABO variants affect the odds of severe disease. Some studies looking directly at blood type, not genetic markers, have reported that type O blood protects against COVID-19, whereas A blood makes a person more vulnerable. It may be that blood type influences whether a person gets infected, but not how sick they get, says Stanford University geneticist Manuel Rivas. In any case, O blood offers at best modest protection. There are a lot of people with O blood that have died of the disease. It doesn't really help you, says geneticist Andre Franke of the Christian-Albrecht University of Kiel, a co-leader of the NEJM study.

Researchers expect to pin down more COVID-19 risk genesalready, after folding in the U.K. data plumbed by Baillie's team, the COVID-19 Host Genetics Initiative has found another hit, a gene called FOXP4 implicated in lung cancer. And in a new med-Rxiv preprint posted last week, the company Ancestry.com reports that a gene previously connected to the effects of the flu may also boost COVID-19 susceptibility only in men, who are more likely to die of the disease than women.

Geneticists have had little luck so far identifying gene variants that explain why COVID-19 has hit Black people in the United States and United Kingdom particularly hard. The chromosome 3 variant is absent in most people of African ancestry. Researchers suspect that socioeconomic factors and preexisting conditions may better explain the increased risks. But several projects, including Baillie's, are recruiting more people of non-European backgrounds to bolster their power to find COVID-19 gene links. And in an abstract for an online talk later this month at the American Society of Human Genetics annual meeting, the company Regeneron reports it has found a genome region that may raise the risk of severe disease mainly in people of African ancestry.

Even as more genetic risk factors are identified, their overall effect on infected people will be modest compared with other COVID-19 factors, Duggal says. But studies like the U.K. team's could help reveal the underlying biology of the disease and inspire better treatments. I don't think genetics will lead us out of this. I think genetics may give us new opportunities, Duggal says.

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Found: genes that sway the course of the coronavirus - Science

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