StemCell Therapy

Despite what many of us might like to believe, COVID-19 has not gone away. South Africa recently identified two new subvariants of Omicron designated BA.4 and BA.5. These subvariants have now spread to several other countries, including the United Kingdom and the United States. Should we be concerned about them? Medical News Today assessed the evidence and spoke to experts in the U.S. and the U.K. to find out.

Alpha, Beta, Gamma, Delta, Omicron the list of SARS-CoV-2 variants continues to expand. And no sooner have we got used to one variant than another appears.

Latest on the list are the Omicron subvariants BA.4 and BA.5, which were identified recently in South Africa, one of the few countries that are still sequencing large numbers of COVID-19 tests.

South Africa has seen a rapid increase in positive tests for COVID-19, and authorities believe that BA.4 and BA.5 are responsible. The National Institute of Clinical Diseases in South Africa reports that BA.4 and BA.5 are Omicron viruses with a new combination of mutations.

Scientists in this country first detected BA.4 on January 10, 2022, and it has since spread throughout South Africa, now making up 35% of positive tests. BA.5 was identified on February 25, and now accounts for 20% of cases in several South African regions.

Both subvariants are similar to Omicron BA.2, which is currently dominant in the U.K., continental Europe, and the U.S.

BA.4 and BA.5 have identical mutations on their spike protein the part of the virus that attaches to receptors on human cells that differentiate them from BA.2. Each subvariant has its own different mutations in other areas of the virus.

We have learned that the [COVID-19-causing variants] are more mutable than we initially thought. Periodically we get major new variants thats a big shift. But we also get little, what we call drift variants. You can think of them as members of the same family [] theyre like cousins.

Prof. William Schaffner, professor of infectious diseases at the Vanderbilt University School of Medicine in Nashville, TN

So far, BA.4 and BA.5 have been identified in several countries in addition to South Africa. According to a report from the U.K. Health Security Agency (UKHSA), with data up to April 22, BA.4 was present in Austria, the U.K., the U.S., Denmark, Belgium, Israel, Germany, Italy, Canada, France, the Netherlands, Australia, Switzerland, and Botswana.

On the same date, health authorities had identified BA.5 in Portugal, Germany, the U.K., the U.S., Denmark, France, Austria, Belgium, Hong Kong, Australia, Canada, Israel, Norway, Pakistan, Spain, and Switzerland.

Few countries are sequencing large numbers of positive tests, despite the Director-General of the World Health Organization (WHO) stating on May 4 that testing and sequencing remain absolutely critical.

In many countries were essentially blind to how the virus is mutating. We dont know whats coming next.

Dr. Tedros Adhanom Ghebreyesus, WHO Director-General

He is not alone in his concern about the lack of sequencing. Prof. Christina Pagel, professor of operational research at University College London (UCL) and director of the UCL Clinical Operational Research Unit, told Medical News Today that [w]e are opening ourselves up to a serious new wave particularly in winter that we would not be able to spot in time.

Although the numbers recorded for both variants are currently low, the actual case numbers are likely to be much higher. Without sequencing of positive tests, the variants that cause COVID-19 cannot be identified.

On May 12, the European Centre for Disease Prevention and Control (ECDC) reclassified BA.4 and BA.5 as variants of concern. This followed a sharp rise in cases in Portugal, where the Portuguese National Institute of Health estimated on May 8 that BA.5 was responsible for around 37% of all positive cases.

The ECDC reports that although there is no evidence yet of increased severity over previous variants, BA.4 and BA.5 do appear to be more transmissible.

The Omicrons are an extraordinarily contagious family. There are some data that say these subvariants are even more contagious. [] Do they have the capacity to produce more severe disease? At the moment, if anything, Omicron seems to be on the milder side.

Prof. William Schaffner

In the U.S., the Centers for Disease Control and Prevention (CDC) have also designated BA.4 and BA.5 as variants of concern.

The U.K. has not yet followed suit. However, the UKHSA published a risk assessment of the two subvariants comparing them with Omicron BA.2. This suggests that the new subvariants may be better at evading the immune system than BA.2, but that the data is insufficient to draw firm conclusions.

In South Africa, which has identified the greatest number of cases, symptoms and severity seem similar to those of disease caused by Omicron BA.2. So far, the number of hospitalizations there has increased only slightly.

Some good news from GAVI the vaccine alliance is that although antibodies from previous Omicron infection do not seem to afford much protection against the new variants, antibodies from vaccination appear to be much more effective.

Prof. Schaffner agreed that vaccines should protect against severe disease from the new variants: These are slightly different mutations of the spike protein are they so different that they cannot be responsive to our vaccines? The answer is no.

However, he is concerned that vaccine fatigue may be having an effect:

Of course, vaccines dont prevent disease vaccination prevents disease. And the issue, at least in [the U.S.], is can we persuade people to come forward yet again to be vaccinated? There is clearly vaccine fatigue out there.

He added that [t]he more people we can vaccinate around the world [the more we can] reduce the chance of these rogue variants popping up.

Prof. Jonathan Stoye, FRS, principal group leader, and international affairs ambassador at the Francis Crick Institute in London, U.K., agreed: It does not seem unreasonable to ask whether a greater emphasis should not be placed on attempting to provide and deliver a vaccine which can be administered to all the worlds unprotected people, particularly those in lower and middle-income countries.

It is likely that BA.4 and BA.5 will spread further, and that they will not be the last new variants.

Prof. Pagel expressed concern that lack of testing and sequencing may mean that variants are not detected early: [I]n England, for instance, we are only really doing PCR tests on hospital admissions [] [and] because admissions are skewed towards older populations, it will take longer for variants to show up if they spread first among children and young people as has been typical so far.

These concerns were echoed by Prof. Schaffner, who said that [w]e require a coordinated international surveillance system, and critical to that is the sequencing of viruses. Number one: To detect these minor subvariants. Its always better to know than not [to] know.

And then, of course, the sequencing is utterly important to pick up that rare event when we would get another rogue strain that could evade the protection of our vaccines, he added.

It is likely that COVID-19, in whatever form, will be with us for some years to come the key question is, can we keep it under control as we try to get life back to normal?

As weve moved from pandemic phase to endemic, how will we cope? Are we going to come to some sort of fraught truce with this virus? We havent figured out how to do that yet.

Prof. William Schaffner

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Omicron BA.4 and BA.5: What to know about the new variants - Medical News Today

BEIJING & CAMBRIDGE, Mass.--(BUSINESS WIRE)--CANbridge Pharmaceuticals Inc. (HKEX:1228), a leading China-based global biopharmaceutical company committed to the research, development and commercialization of transformative rare disease and rare oncology therapies, announced the presentation of the initial data from its gene therapy research agreement with the Horae Gene Therapy Center, at the UMass Chan Medical School, at the ASGCT 25th Annual Meeting, in Washington DC, today.

In work led by Jun Xie Ph.D., in the lab of Guangping Gao, Ph.D., researchers concluded that a novel second-generation scAAV9 gene therapy, expressing co-hSMN1 from an endogenous hSMN1 promoter, demonstrated superior potency, efficacy and safety in mice with spinal muscular atrophy (SMA), compared to the benchmark vector, scAAV9-CMVen/CB-hSMN1, which is similar to the vector used in the gene therapy approved by the US Food and Drug Administration for the treatment of SMA.

The novel second-generation gene therapy showed superior efficacy to the benchmark vector in SMA mice along several endpoints, including extended lifespan, restored muscle function and better neuromuscular junction innervation, without the liver toxicity shown in the benchmark-treated animals. Specifically, the second-generation gene therapy significantly extended the lifespan of SMA mice in a dose-dependent manner, with all doses showing improved survival, compared to both the benchmark gene therapy vector high dose and to untreated SMA mice. The second-generation gene therapy also restored muscle function in SMA mice significantly better than the benchmark vector. This was observed in both the righting test, in which second-generation gene therapy-treated SMA mice were able to right themselves faster than the benchmark vector-treated mice, and in the grid test, in which they demonstrated better muscle function. In addition, the second-generation vector restored the innervation of the neuromuscular junctions in SMA mice to close to that of wild-type mice, and significantly better than in SMA mice treated with the benchmark vector.

Finally, SMA mice treated with the second-generation gene therapy showed higher SMN1 expression in the central nervous system and lower peripheral tissue than the benchmark vector-treated mice, in a pattern that was similar to that of healthy carrier mice. Furthermore, the benchmark vector produced liver damage in four out of seven SMA mice, eight days post-injection, compared to no liver toxicity in mice treated with the second-generation gene therapy vector, or in healthy carrier mice, suggesting that the second-generation gene therapy has the potential to reduce liver toxicity and overcome current therapeutic limitations.

This is the first data to be presented from the gene therapy research collaboration between CANbridge and the Gao Lab at the Horae Gene Therapy Center.

What differentiates our novel second-generation gene therapy vector from the benchmark vector is the genetic engineering of a codon-optimized SMN1 transgene under the control of the endogenous SMN1 promoter, which enables highly efficient and regulated gene expression across tissues, with the potential to improve both efficacy and safety, while at a lower dose than is currently used in patients, said Yunxiang Zhu, Ph.D., Vice President, Head of Global Research, CANbridge Pharmaceuticals, and a study author. These data encourage us to support the continued development of this second-generation vector as a potential best-in-class gene therapy for SMA.

We are seeking to develop a next-generation gene therapy for SMA that leverages the advances in gene therapy that have occurred since the first gene therapy was developed, over a decade ago, said Guangping Gao, Ph.D., Co-Director, Li Weibo Institute for Rare Diseases Research, Director, the Horae Gene Therapy Center and Viral Vector Core, Professor of Microbiology and Physiological Systems and Penelope Booth Rockwell Professor in Biomedical Research at UMass Chan Medical School, and a lead study author. Dr. Gao is also a former ASCGT president.

Presentation Details:

Title: Endogenous Human SMN1 Promoter-driven Gene Replacement Improves the Efficacy and Safety of AAV9-mediated Gene Therapy for Spinal Muscular Atrophy in Mice

Poster #: M-144

Category: Neurologic Diseases: AAV Vectors- Preclinical and Proof-of-Concept Studies

Category: Neurologic Diseases I

Session Date and Time: Monday, May 16, 5:30-6:30 PM EDT

Authors: Qing Xie, Hong Ma, Xiupeng Chen, Yunxiang Zhu, Yijie Ma, Leila Jalinous, Qin Su, Phillip Tai, Guangping Gao, Jun Xie

Abstracts are available on the ASGCT website: https://annualmeeting.asgct.org/abstracts

About the Horae Gene Therapy Center at UMass Chan Medical School

The faculty of the Horae Gene Therapy Center is dedicated to developing therapeutic approaches for rare inherited disease for which there is no cure. We utilize state of the art technologies to either genetically modulate mutated genes that produce disease-causing proteins or introduce a healthy copy of a gene if the mutation results in a non-functional protein.

The Horae Gene Therapy Center faculty is interdisciplinary, including members from the departments of Pediatrics, Microbiology & Physiological Systems, Biochemistry & Molecular Pharmacology, Neurology, Medicine and Ophthalmology. Physicians and PhDs work together to address the medical needs of rare diseases, such as Alpha 1-Antitrypsin Deficiency, Canavan Disease, Tay-Sachs and Sandhoff diseases, Retinitis Pigmentosa, Cystic fibrosis, Lou Gehrig's disease, TNNT1 nemaline myopathy, Rett syndrome, N-Gly 1 deficiency, Pitt-Hopkins syndrome, Marple Syrup Urine Disease, Sialidosis, GM3 synthase deficiency, Huntington's disease, ALS and others. More common diseases such as cardiac arrhythmia and hypercholesterolemia are also investigated. The hope is to treat a wide spectrum of diseases by various gene therapeutic approaches. Additionally, the University of Massachusetts Chan Medical School conducts clinical trials on site and some of these trials are conducted by the investigators at the Gene Therapy center.

About CANbridge Pharmaceuticals Inc.

CANbridge Pharmaceuticals Inc. (HKEX:1228) is a China-based global biopharmaceutical company committed to the research, development and commercialization of transformative therapies for rare disease and rare oncology. CANbridge has a differentiated drug portfolio, with three approved drugs and a pipeline of 11 assets, targeting prevalent rare disease and rare oncology indications that have unmet needs and significant market potential. These include Hunter syndrome and other lysosomal storage disorders, complement-mediated disorders, hemophilia A, metabolic disorders, rare cholestatic liver diseases and neuromuscular diseases, as well as glioblastoma multiforme. CANbridge is also building next-generation gene therapy development capability through a combination of collaboration with world-leading researchers and biotech companies and internal capacity. CANbridge global partners include: Apogenix, GC Pharma, Mirum, Wuxi Biologics, Privus, the UMass Chan Medical School and LogicBio.

For more on CANbridge Pharmaceuticals Inc., please go to: http://www.canbridgepharma.com.

Forward-Looking Statements

The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, we undertake no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, after the data on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development.

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CANbridge-UMass Chan Medical School Gene Therapy Research Presented at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting - Business...

PITTSBURGH, May 19, 2022 (GLOBE NEWSWIRE) -- Krystal Biotech, Inc. (the Company) (NASDAQ: KRYS), the leader in redosable gene therapy, is pleased to present new data entitled GEM-3: phase 3 safety and immunogenicity results of beremagene geperpavec (B-VEC), an investigational, topical gene therapy for dystrophic epidermolysis bullosa (DEB) at the Society for Investigative Dermatology 2022 Annual Meeting, taking place May 18-21 in Portland, Oregon.

Krystal Presentation

GEM-3: phase 3 safety and immunogenicity results of beremagene geperpavec (B-VEC), an investigational, topical gene therapy for dystrophic epidermolysis bullosa (DEB)M. Peter Marinkovich, MD, FAADPoster Session 1Date & Time: Thursday, May 19, 4:30-6:30pm PDT

ePoster Presentation: Session 2, Genetic Disease, Gene Regulation, and Gene TherapyDate & Time: Friday, May 20, 5:54-6:00pm PDT

The poster and ePoster will be available to conference attendees. To register for the conference, please visit SID 2022 Annual Meeting | Society for Investigative Dermatology. The Company will be present at Booth 218 to educate about DEB and the mechanism of the disease. Following the presentation, materials will be available to view online on the Investor section of the Companys website.

About Dystrophic Epidermolysis Bullosa (DEB)DEB is a rare and severe disease that affects the skin and mucosal tissues. It is caused by one or more mutations in a gene calledCOL7A1, which is responsible for the production of the protein type VII collagen (COL7) that forms anchoring fibrils that bind the dermis (inner layer of the skin) to the epidermis (outer layer of the skin). The lack of functional anchoring fibrils in DEB patients leads to extremely fragile skin that blisters and tears from minor friction or trauma. DEB patients suffer from open wounds, which leads to skin infections, fibrosis which can cause fusion of fingers and toes, and ultimately an increased risk of developing an aggressive form of squamous cell carcinoma which, in severe cases, can be fatal.

About B-VECB-VECis an investigational non-invasive, topical, redosable gene therapy designed to deliver two copies of theCOL7A1gene when applied directly to DEB wounds. B-VEC was designed to treat DEB at the molecular level by providing the patients skin cells the template to make normal COL7 protein, thereby addressing the fundamental disease-causing mechanism.

TheU.S. Food and Drug Administration(FDA) and theEuropean Medicines Agency(EMA) have each granted B-VEC an orphan drug designation for the treatment of DEB. The FDA has also granted B-VECfast track designation and rare pediatric designation for the treatment of DEB. In addition, in 2019, the FDA granted Regenerative Medicine Advanced Therapy (RMAT) to B-VEC for the treatment of DEB and the EMA granted PRIority MEdicines ("PRIME") eligibility for B-VECto treat DEB.

About Krystal Biotech, Inc.Krystal Biotech, Inc. (NASDAQ: KRYS) is a pivotal-stage gene therapy company leveraging its proprietary, redosable gene therapy platform and in-house manufacturing capabilities to develop life-changing medicines for patients with serious diseases, including rare diseases in skin, lung, and other areas. For more information please visit http://www.krystalbio.com, and follow @KrystalBiotech on LinkedIn and Twitter.

CONTACTS:Investors and Media:Meg DodgeKrystal Biotechmdodge@krystalbio.com

Source: Krystal Biotech, Inc.

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Krystal Biotech to Present Additional Data on B-VEC from the GEM-3 Phase 3 Study at the Society for Investigative Dermatology Annual Meeting -...

Mounjaro delivered superior A1C reductions versus all comparators in phase 3 SURPASS clinical trials

While not indicated for weight loss, Mounjaro led to significantly greater weight reductions versus comparators in a key secondary endpoint

Mounjaro represents the first new class of diabetes medicines introduced in nearly a decade and is expected to be available in the U.S. in the coming weeks

INDIANAPOLIS, May 13, 2022 /PRNewswire/ -- The U.S. Food and Drug Administration (FDA) approved Mounjaro (tirzepatide) injection, Eli Lilly and Company's (NYSE: LLY) new once-weekly GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Mounjaro has not been studied in patients with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes mellitus.

As the first and only FDA-approved GIP and GLP-1 receptor agonist, Mounjaro is a single molecule that activates the body's receptors for GIP and GLP-1, which are natural incretin hormones.1

"Mounjaro delivered superior and consistent A1C reductions against all of the comparators throughout the SURPASS program, which was designed to assess Mounjaro's efficacy and safety in a broad range of adults with type 2 diabetes who could be treated in clinical practice. The approval of Mounjaro is an exciting step forward for people living with type 2 diabetes given the results seen in these clinical trials," said Juan Pablo Fras, M.D., Medical Director, National Research Institute and Investigator in the SURPASS program.

Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly's well-established auto-injector pen with a pre-attached, hidden needle that patients do not need to handle or see.

The approval was based on results from the phase 3 SURPASS program, which included active comparators of injectable semaglutide 1 mg, insulin glargine and insulin degludec. Efficacy was evaluated for Mounjaro5 mg, 10 mg and 15 mg used alone or in combination with commonly prescribed diabetes medications, including metformin, SGLT2 inhibitors, sulfonylureas and insulin glargine. Participants in the SURPASS program achieved average A1C reductions between 1.8% and 2.1% for Mounjaro 5 mg and between 1.7% and 2.4% for both Mounjaro 10 mg and Mounjaro 15 mg. While not indicated for weight loss, mean change in body weight was a key secondary endpoint in all SURPASS studies. Participants treated with Mounjaro lost between 12 lb. (5 mg) and 25 lb. (15 mg) on average.1

Side effects reported in at least 5% of patients treated with Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion (dyspepsia), and stomach (abdominal) pain. The labeling for Mounjaro contains a Boxed Warning regarding thyroid C-cell tumors. Mounjaro is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.1

"Lilly has a nearly 100-year heritage of advancing care for people living with diabetes never settling for current outcomes. We're not satisfied knowing that half of the more than 30 million Americans living with type 2 diabetes are not reaching their target blood glucose levels," said Mike Mason, president, Lilly Diabetes. "We are thrilled to introduce Mounjaro, which represents the first new class of type 2 diabetes medication introduced in almost a decade and embodies our mission to bring innovative new therapies to the diabetes community."

Mounjaro is expected to be available in the United States in the coming weeks. Lilly is committed to helping people access the medicines they are prescribed and will work with insurers, health systems and providers to help enable patient access to Mounjaro. Lilly plans to offer a Mounjaro savings card for people who qualify. Patients or healthcare professionals with questions about Mounjaro can visit http://www.Mounjaro.com or call The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979).

Tirzepatide is also under regulatory review for the treatment of type 2 diabetes in Europe, Japan and several additional markets. A multimedia gallery is available on Lilly.com.

About the SURPASS clinical trial programThe SURPASS phase 3 global clinical development program for tirzepatide began in late 2018 and included five global registration trials and two regional trials in Japan. These studies ranged from 40 to 52 weeks and evaluated the efficacy and safety of Mounjaro 5 mg, 10 mg and 15 mg as a monotherapy and as an add-on to various standard-of-care medications for type 2 diabetes. The active comparators in the studies were injectable semaglutide 1 mg, insulin glargine and insulin degludec. Collectively, the five global registration trials consistently demonstrated A1C reductions for participants taking Mounjaro across multiple stages of their type 2 diabetes journeys, from an average around five to 13 years of having diabetes.2-8

*p<0.001 for superiority vs. placebo or active comparator, adjusted for multiplicityp<0.05 for superiority vs. semaglutide 1 mg, adjusted for multiplicity

About Mounjaro (tirzepatide) injection1Mounjaro (tirzepatide) injection is FDA-approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. As the first and only FDA-approved GIP and GLP-1 receptor agonist, Mounjaro is a single molecule that activates the body's receptors for GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1). Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly's well-established auto-injector pen with a pre-attached, hidden needle that patients do not need to handle or see.

PURPOSE AND SAFETY SUMMARY WITH WARNINGSImportant Facts About MounjaroTM (mown-JAHR-OH). It is also known as tirzepatide.

WarningsMounjaro may cause tumors in the thyroid, including thyroid cancer. Watch for possible symptoms, such as a lump or swelling in the neck, hoarseness, trouble swallowing, or shortness of breath. If you have a symptom, tell your healthcare provider.

Mounjaro may cause serious side effects, including:

Inflammation of the pancreas (pancreatitis). Stop using Mounjaro and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.

Low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Mounjaro with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include dizziness or light-headedness, sweating, confusion or drowsiness, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger, weakness and feeling jittery.

Serious allergic reactions. Stop using Mounjaro and get medical help right away if you have any symptoms of a serious allergic reaction, including swelling of your face, lips, tongue or throat, problems breathing or swallowing, severe rash or itching, fainting or feeling dizzy, and very rapid heartbeat.

Kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.

Severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use Mounjaro. Tell your healthcare provider if you have stomach problems that are severe or will not go away.

Changes in vision. Tell your healthcare provider if you have changes in vision during treatment with Mounjaro.

Gallbladder problems. Gallbladder problems have happened in some people who use Mounjaro. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include pain in your upper stomach (abdomen), fever, yellowing of skin or eyes (jaundice), and clay-colored stools.

Common side effectsThe most common side effects of Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion, and stomach (abdominal) pain. These are not all the possible side effects of Mounjaro. Talk to your healthcare provider about any side effect that bothers you or doesn't go away.

Tell your healthcare provider if you have any side effects. You can report side effects at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

Before using

Review these questions with your healthcare provider:

How to take

Learn moreFor more information, call 1-800-LillyRx (1-800-545-5979) or go towww.mounjaro.com.

This information does not take the place of talking with your healthcare provider. Be sure to talk to your healthcare provider about Mounjaro and how to take it. Your healthcare provider is the best person to help you decide if Mounjaro is right for you.

MounjaroTM and its delivery device base are trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

Please click to access full Prescribing Informationand Medication Guide.

TR CON CBS MAY2022

About LillyLilly unites caring with discovery to create medicines that make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 47million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer's disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visitLilly.comandLilly.com/newsroomor follow us onFacebook,Instagram, Twitterand LinkedIn. P-LLY

Lilly Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Mounjaro (tirzepatide 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and 15 mg) injection as a treatment to improve glycemic control in adults with type 2 diabetes, the timeline for supply of Mounjaro to become available, and certain other milestones and ongoing clinical trials of Mounjaro and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product or medical device, there are substantial risks and uncertainties in the process of research, development and commercialization. Among other things, there can be no guarantee thatMounjarowill be commercially successful,that future study results will be consistent with results to date, or that we will meet our anticipated timelines for the commercialization of Mounjaro. For further discussion of these and other risks and uncertainties, see Lilly's most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

References

PP-TR-US-0125 05/2022 Lilly USA, LLC 2022. All rights reserved.

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FDA approves Lilly's Mounjaro (tirzepatide) injection, the first and only GIP and GLP-1 receptor agonist for the treatment of adults with type 2...

Sitting atop each kidney and measuring only around two centimeters long, the adrenal glands are tiny but mighty. These glands produce steroid hormones, including those involved in stress response, blood pressure maintenance, and fertility. When their development goes awry, it can cause a life-threatening condition called primary adrenal insufficiency, also known as Addisons disease. Many of the genetics involved in this and other adrenal gland disorders remain unknown.

Research on adrenal glands has often relied on insights made using mouse models. Now, a new study led by the School of Veterinary Medicines Kotaro Sasaki, which examined the developmental origin of the glands in humans and nonhuman primates, finds key developmental differences. This new understanding may inform diagnostics and treatment for Addisons disease and other endocrine system disorders.

The work was published in the journal Science Advances.

While some genetic causes of primary adrenal insufficiency have been identified, the mechanism has remained poorly understood, says Sasaki. Our findings help in identifying genes involved in adrenal development and could lead to new targets for therapeutic intervention.

Sasakis investigations have centered around studied gonadal development, how cells become ovaries or testes, organs that, like the adrenal gland, release hormones. Given this background, the adrenal gland was a natural next focus, especially because it has a shared origin with the gonads. In their recent work, Sasaki and colleagues looked at some of the earliest developmental stages to see how precursor cells and tissues evolve to give rise to the adrenal gland.

Scientists have long known that both the gonads and adrenal gland develop from a tissue known as the coelomic epithelium (CE), which is present at an early stage of embryonic development. In mice, for example, this tissue develops into the adrenogonadal primordium, which later divides to form both the adrenal primordium and the gonadal progenitor. The adrenal primodium goes on to become the adrenal gland, and the gonadal progenitor develops into either ovaries or testes.

Using immunofluorescence and in situ hybridization analyses, in which markers enable scientists to track cells descendants, Sasaki and his team found that primate CE expressed different genes than mouse CE. Whereas mice expressed the WT1, GATA4, and NR5A1 genes within the adrenogonadal primordium, primates did not express GATA4 in a parallel stage of development, a surprise to the researchers.

Whats more, while one portion of the primate CE led to the gonadal precursor, the other developed into the adrenal gland precursors, a division that wasnt present in mice.

It takes place in a way thats totally different from the mouse, says Sasaki. It appears that the portion of the coelomic epithelium that gives rise to the gonads is spatially separated from the part that gives rise to the adrenal gland.

Single-cell sequencing further revealed different patterns of gene expression between the adrenal and gonadal cell lineages, as well as a clear divergence between humans and mice. Some of these differentially expressed genes, Sasaki notes, are likely important in the process of deriving adrenal or gonadal tissues from CE.

Certain genes, Sasaki says, could also be examined in the context of adrenal insufficiency.

Currently, people with Addisons disease are treated with a lifelong steroid replacement therapy, using synthetic hormones to substitute for those that their bodies cant make on their own. Its not a cure and comes with serious side effects, Sasaki says.

In future work, he and colleagues hope to lay the groundwork in the lab to generate the adrenal cortex, employing inducible pluripotent stem cells, cells derived from blood or skin that can be induced to become a variety of different cell types. With such an approach, they could coax the stem cells to follow the normal developmental pathway toward becoming adrenal tissue. While in its early stages, this could enable a cell-based therapy for primary adrenal insufficiency, ideally avoiding some of the drawbacks of hormone replacement therapy.

Were pursuing in vitro studies to continue mapping out a blueprint that could be applicable to humans, Sasaki says.

Kotaro Sasaki is an assistant professor in the Department of Biomedical Sciences at the University of Pennsylvania School of Veterinary Medicine.

Sasakis coauthors were Penn Vets Keren Cheng, Yasunari Seita, Taku Moriwaki, Yuka Sakata, and Young Sun Hwang; Kiwamu Noshiro, Hidemichi Watari, and Takeshi Umazume of Hokkaido University; Toshihiko Torigoe of Sapporo Medical University; Mitinori Saitou of Kyoto University; Hideaki Tsuchiya and Chizuru Iwatani of Shiga University of Medical Science; Masayoshi Hosaka of the Fukuzumi Obstetrics and Gynecology Hospital; and Toshihiro Ohkouchi of Ohkouchi Obstetrics and Gynecology Hospital.

Sasaki was corresponding author and Cheng, Seita, and Moriwaki were co-first authors of the work, which was supported in part by the Japanese Science and Technology Agency (grants JPMJCE1301 and JPMJER1104), Silicon Valley Community Foundation, and Good Ventures Foundation.

The rest is here:
Elucidating the developmental origin of life-sustaining adrenal glands | Penn Today - Penn Today

Four years ago, a small Philadelphia biotech company won U.S. approval for the first gene therapy to treat an inherited disease, a landmark after decades of research aimed at finding ways to correct errors in DNA.

Since then, most of the world's largest pharmaceutical companies have invested in gene therapy, as well as cell therapies that rely on genetic modification. Dozens of new biotech companies have launched, while scientists have taken forward breakthroughs in gene editing science to open up new treatment possibilities.

But the confidence brought on by such advances has also been tempered by safety setbacks and clinical trial results that fell short of expectations. In 2022, the outlook for the field remains bright, but companies face critical questions that could shape whether, and how soon, new genetic medicines reach patients. Here are five:

Food and Drug Administration approval of Spark Therapeutics' blindness treatment Luxturna a first in the U.S. came in 2017. A year and a half later, Novartis' spinal muscular atrophy therapy Zolgensma won a landmark OK.

But none have reached market since, with treatments from BioMarin Pharmaceutical and Bluebird bio unexpectedly derailed or delayed.

That could change in 2022. Two of Bluebird's treatments, for the blood disease beta thalassemia and a rare brain disorder, are now under review by the FDA, with target decision dates in May and June. BioMarin, after obtaining more data for its hemophilia A gene therapy, plans to soon approach the FDA about resubmitting an application for approval.

Others, such as CSL Behring and PTC Therapeutics, are also currently planning to file their experimental gene therapies with the FDA in 2022.

Approvals, should they come, could provide important validation for their makers and expand the number of patients for whom genetic medicines are an option. In biotech, though, approvals aren't the end of the road, but rather the mark of a sometimes challenging transition from research to commercial operations. With price tags expected to be high, and still outstanding questions around safety and long-term benefit, new gene therapies may prove difficult to sell.

A record $20 billion flowed into gene and cell therapy developers in 2020, significantly eclipsing the previous high-water mark set in 2018.

Last year, the bar was set higher still, with a total of $23 billion invested in the sector, according to figures compiled by the Alliance for Regenerative Medicine. About half of that funding went toward gene therapy developers specifically, with a similar share going to cell-based immunotherapy makers.

Driving the jump was a sharp increase in the amount of venture funding, which rose 73% to total nearly $10 billion, per ARM. Initial public offerings also helped, with sixteen new startups raising at least $50 million on U.S. markets.

Entering 2022, the question facing the field is whether those record numbers will continue. Biotech as a whole slumped into the end of last year, with shares of many companies falling amid a broader investment pullback. Gene therapy developers, a number of which had notable safety concerns crop up over 2021, were hit particularly hard.

Moreover, many startups that jumped to public markets hadn't yet begun clinical trials roughly half of the 29 gene and cell therapy companies that IPO'd over the past two years were preclinical, according to data compiled by BioPharma Dive. That can set high expectations companies will be hard pressed to meet.

Generation Bio, for example, raised $200 million in June 2020 with a pipeline of preclinical gene therapies for rare diseases of the liver and eye. Unexpected findings in animal studies, however, sank company shares by nearly 60% last December.

Still, the pace of progress in gene and cell therapy is fast. The potential is vast, too, which could continue to support high levels of investment.

"I think fundamentally, investment in this sector is driven by scientific advances, and clinical events and milestones," said Janet Lambert, ARM's CEO, in an interview. "And I think we see those in 2022."

The potential of replacing or editing faulty genes has been clear for decades. How to do so safely has been much less certain, and concerns on that front have set back the field several times.

"Safety, safety and safety are the first three top-of-mind risks," said Luca Issi, an analyst at RBC Capital Markets, in an interview.

Researchers have spent years making the technology that underpins gene therapy safer and now have a much better understanding of the tools at their disposal. But as dozens of companies push into clinical trials, a number of them have run into safety problems that raise crucial questions for investigators.

In trials run by Audentes Therapeutics and by Pfizer (in separate diseases), study volunteers have tragically died for reasons that aren't fully understood. UniQure, Bluebird bio and, most recently, Allogene Therapeutics have reported cases of cancer or worrisome genetic abnormalities that triggered study halts and investigations.

While the treatments being tested were later cleared in the three latter cases, the FDA was sufficiently alarmed to convene a panel of outside experts to review potential safety risks last fall. (Bluebird recently disclosed a new hold in a study of its sickle cell gene therapy due to a patient developing chronic anemia.)

The meeting was welcomed by some in the industry, who hope to work with the FDA to better detail known risks and how to avoid them in testing.

"[There's] nothing better than getting people together and talking about your struggles, and having FDA participate in that," said Ken Mills, CEO of gene therapy developer Regenxbio, in an interview. "The biggest benefit probably is for the new and emerging teams and people and companies that are coming into this space."

Safety scares and setbacks are likely to happen again, as more companies launch additional clinical trials. The FDA, as the recent meeting and clinical holds have shown, appears to be carefully weighing the potential risks to patients.

But, notably, there hasn't been a pullback from pursuing further research, as has happened in the past. Different technologies and diseases present different risks, which regulators, companies and the patient community are recognizing.

"We're by definition pushing the scientific envelope, and patients that we seek to treat often have few or no other treatment options," said ARM's Lambert.

Last June, Intellia Therapeutics disclosed early results from a study that offered the first clinical evidence CRISPR gene editing could be done safely and effectively inside the body.

The data were a major milestone for a technology that's dramatically expanded the possibility for editing DNA to treat disease. But the first glimpse left many important questions unanswered, not least of which are how long the reported effects might last and whether they'll drive the kind of dramatic clinical benefit gene editing promises.

Intellia is set to give an update on the study this quarter, which will start to give a better sense of how patients are faring. Later in the year the company is expecting to have preliminary data from an early study of another "in vivo" gene editing treatment.

In vivo gene editing is seen as a simpler approach that could work in more diseases than treatments that rely on stem cells extracted from each patient. But it's also potentially riskier, with the editing of DNA taking place inside the body rather than in a laboratory.

Areas like the eye, which is protected from some of the body's immune responses, have been a common first in vivo target by companies like Editas Medicine. But Intellia and others are targeting other tissues like the liver, muscle and lungs.

Later this year, Verve Therapeutics, a company that uses a more precise form of gene editing called base editing, plans to treat the first patient with an in vivo treatment for heart disease (which targets a gene expressed in the liver.)

"The future of gene editing is in vivo," said RBC's Issi. His view seems to be shared by Pfizer, which on Monday announced a $300 million research deal with Beam Therapeutics to pursue in vivo gene editing targets in the liver, muscle and central nervous system.

With more and more cell and gene therapy companies launching, the pipeline of would-be therapies has grown rapidly, as has the number of clinical trials being launched.

Yet, many companies are exploring similar approaches for the same diseases, resulting in drug pipelines that mirror each other. A September 2021 report from investment bank Piper Sandler found 21 gene therapy programs aimed at hemophilia A, 19 targeting Duchenne muscular dystrophy and 18 going after sickle cell disease.

In gene editing, Intellia, Editas, Beam and CRISPR Therapeutics are all developing treatments for sickle cell disease, with CRISPR the furthest along.

As programs advance and begin to deliver more clinical data, companies may be forced into making hard choices.

"[W]e think investors will place greater scrutiny as programs enter the clinic and certain rare diseases are disproportionately pursued," analysts at Stifel wrote in a recent note to investors, citing Fabry disease and hemophilia in particular.

This January, for example, Cambridge, Massachusetts-based Avrobio stopped work on a treatment for Fabry that was, until that point, the company's lead candidate. The decision was triggered by unexpected findings that looked different than earlier study results, but Avrobio also cited "multiple challenging regulatory and market dynamics."

Read the rest here:
5 questions facing gene therapy in 2022 - BioPharma Dive

It was either die or do this transplant, Mr. Bennett said before the surgery, according to officials at the University of Maryland Medical Center. I want to live. I know its a shot in the dark, but its my last choice.

Dr. Griffith said he first broached the experimental treatment in mid-December, a memorable and pretty strange conversation.

I said, We cant give you a human heart; you dont qualify. But maybe we can use one from an animal, a pig, Dr. Griffith recalled. Its never been done before, but we think we can do it.

I wasnt sure he was understanding me, Dr. Griffith added. Then he said, Well, will I oink?

Xenotransplantation, the process of grafting or transplanting organs or tissues from animals to humans, has a long history. Efforts to use the blood and skin of animals go back hundreds of years.

In the 1960s, chimpanzee kidneys were transplanted into some human patients, but the longest a recipient lived was nine months. In 1983, a baboon heart was transplanted into an infant known as Baby Fae, but she died 20 days later.

Pigs offer advantages over primates for organ procurements, because they are easier to raise and achieve adult human size in six months. Pig heart valves are routinely transplanted into humans, and some patients with diabetes have received porcine pancreas cells. Pig skin has also been used as a temporary graft for burn patients.

Two newer technologies gene editing and cloning have yielded genetically altered pig organs less likely to be rejected by humans. Pig hearts have been transplanted successfully into baboons by Dr. Muhammad Mohiuddin, a professor of surgery at University of Maryland School of Medicine who established the cardiac xenotransplantation program with Dr. Griffith and is its scientific director. But safety concerns and fear of setting off a dangerous immune response that can be life-threatening precluded their use in humans until recently.

Link:
In a First, Man Receives a Heart From a Genetically Altered Pig - The New York Times

By Allison Proffitt

January 13, 2022 | At the JP Morgan Healthcare Conferencebeing held virtually again this yearpharma and biotech companies gave overviews of their 2021 business and their views of the future. Here are the highlights we noted from presentations from Regeneron, 10X Genomics, and Invitae

Regeneron: Investing in Antibodies

Regeneron CEO and founder Leonard Schleifer reported 20% top line growth for the company in 2021if you exclude their covid antibodies. With the REGEN-COV monoclonal antibody treatment for Covid-19, the company saw 83% growth year over year.

Schleifer touted diversified growth drivers for Regeneron in the future. Their oncology suite has seen success, they said, and they particularly highlighted opportunities to reach oncology targets via drug combinations.

Co-founder and CSO George Yancopoulos spent his time highlighting the Regeneron Genetics Center, which has sequenced more than two million volunteers to date, all of whom have linked their electronic health record to the genetic data, he said. The work has already led to genetic drug targets and changes in clinical trial design, he added.

He emphasized the future of the Regeneron Genetic Medicine initiative, taking the data gleaned from the RGC and combining it with external partner expertise to develop genomic medicines. Partnerships are a key strategy in Regenerons efforts here, and Yancopoulos mentioned Alnylam, Intellia, and Decibel specifically. We are well-positioned to be at the forefront of the next wave of biotech innovation. While still in its infancy, we think that these ground-breaking technologies such as siRNAs, CRISPR-based therapies, as well as virally-directed gene therapy have the potential to be just as large as the biologics are today, Yancopoulos said.

But perhaps the largest target in Regenerons future plans are Covid-19 antibodies. The biggest growth driver for the company last year is essential to overcoming the pandemic, argued Yancopoulos. The most vulnerable part of the entire population, the immunocompromised, which represent about 5-10 million people in America alone, dont respond wellor at all!to vaccines. If youre giving everybody else boosters twice a year, what are you going to be doing for these people who are more vulnerable because they dont have any ability to fight back to the virus, he said. This is where we think essentially giving them a surrogate immune systema surrogate antibody responsesuch as we can with our monoclonal antibodies can really help these individuals.

10X Genomics: News for In Situ

Serge Saxonov, CEO and co-founder of 10X Genomics, summarized the landscape of single-cell sequencing and announced a new in situ product. Weve been making significant advances across many different areas spanning hardware, chemistry, and softwarepushing the state of the artand we will put these advances into the new platform we will bring to market, Saxonov said.

The new Xenium platform will be a single molecule RNA and protein platform offering subcellular resolution, high-throughput, analysis suite, and pre-designed and custom panels. Saxonov declined to give further details, but said a technology access program is expected for 2022 and commercial availability in 2023. It will be designed for ease of use, robustness, and throughput. As will all our products, our overarching goal for Xenium is that it just works, he added.

It was a refrain he mentioned several times as evidence for 10Xs success. We dont constrain our thinking to any particular technology or any particular platform. We start with biology, think critically about where the world is going, what are the big questions, the big capabilities that the world is going to need, and we work backward to figure out what technologies and products were going to build, Saxonov said. We strive to delight our customers. One thing that were particularly proud of is that our customers often tell us that our products just work. That quality, that ease-of-use is actually a result of tons of innovation and advanced technology innovation that goes into making our products. We do the hard work on the backend so for the customer its easy. It just works.

Besides Xenium, Saxonov focused on highlighting ease-of-use improvements to the companys Chromium and Visium platforms. For Chromium, 10X is launching new kits to enable analysis of fixed tissues. In general, samples need to be collected, packaged, transported, and prepared for single-cell analysis, all within a day or less to maintain cell viability, Saxonov said. The companys new Fixed RNA Profiling Kit will let users fix tissues at time of collection, so the patterns of gene and protein expression are chemically frozen in place, he said, using a common fixation technique along with new assay chemistry. Once the tissue is fixed, samples can be shipped, stored, and processed in batch without rush. We expect this product to be a significant enabler, especially for translational and pharma customers, Saxonov said. Its expected to be available mid-2022.

He also announced two antibody and T-cell receptor products, both of which will be available in the second half of 2022. BEAM-Ab enables general antibody discovery and BEAM-T empowers discovery of optimal T cells for hyper-personalized cancer cell therapy. Now, Saxonov said, anyone will be able to discovery excellent antibodies with minimal effort.

For Visium, 10Xs spatial genomics platform, Saxonov announced Visium CytAssist coming later this year. The hardware tool is meant to bridge the worlds of histology and genomics by transferring molecules from pre-mounted standard glass slides to Visium slides, simplifying sample handling and adapting Visium to pre-existing histology workflows.

At the place and time of their choosing, the customer can preview and choose the best tissue section for their Visium assay, and initiate Visium workflow through CytAssist, Saxonov said. CytAssist will open up tissue sample archives currently stored on glass slides for Visium analysis.

Invitae: Launching A Patient-Owned Data Network

Sean George announced Invitaes new open-ended, multi-sided, patient-owned and controlled network of data to be used to increase the utility of the genomic information. Built on top of Invitaes September acquisition of Ciitizen for $325 million, the Ciitizen Patient Network is available now to Invitaes business partners and individuals and will help pool health information in one place for patients to use as they wish. Whats really important about this, George repeated, is that, it is 100% patient owned, patient controlled, consented, and fully trusted. Wherever that information is going to go, it will be at the behest of the patient and only at the behest of the patient.

The network is the next step in Invitaes longstanding vision of genome management, George said. Its not so much about a single test itself, but about a package of information that can be delivered to the right place at the right time.

For several care areasnewborn and rare disease, reproductive and womens health, and oncologyGeorge reported that by the end of the year, Invitae will have the most comprehensive offering on the market for risk testing, counseling tools, therapy selection, and next steps and monitoring. He flagged cardiovascular disease, neurodegenerative disease, and pharmacogenomics as areas for future investment and develop for Invitae.

The companys efforts to create a platform of tests and counseling options and build a network of partners have laid the groundwork for sharing genetics on a global scale to diagnose more patients and bring therapies to market earlier.

We do presently have some of our own testing competitors accessing that data and running analyses on it to whatever ends. Its up to them and to the patients that own that data. But we believe that is the nature of this kind of network that has to be in place to really drive us into genome management in the future, George said.

At the genome management phase of the platform, George predicts costs will be driven down and data will moved into the hands of ecosystem players that can develop more therapies. We have ambitions, in the future, not just to work with healthcare ecosystem partners, not just to work with healthcare data partners, but eventuallyas we move into the era of genome managementit is all of retail, all of tech, anybody with a device, anybody who can bring anything to the table to help an individual understand and navigate a specific point of their healthcare journey, he said. We believe that this kind of patient network will be fundamental in enabling that in the future, and we couldnt be more excited to be launching this today.

Link:
Antibodies, Easy Single-Cell, Genomics for All: Notes from the JP Morgan Healthcare Conference - Bio-IT World

What if we could help threatened wildlife better adapt to the intractable threats many species are facing from challenges like climate change and disease?

The United Nations has warned that about a million animal and plant species are at risk of extinction. In response, conservation breeding programs are ramping up to boost and protect populations.

The problem is that while conservation breeding can prevent extinction, it doesnt allow threatened species to survive in the wild in the face of these difficult to mitigate threats.

So, while it is critical that we address climate change and diseases, we also need to be urgently looking at way to make it easier for species to live with the threats.

This is where Targeted Genetic Intervention (TGI) comes in.

TGI works by adapting methods that are successfully used in agriculture and medicine in which an individuals genetics are tweaked in ways that, when passed on to the wider population through breeding, can change the traits of a species to improve its survival.

Read more

Two of the most promising approaches in this toolkit include artificial selection and synthetic biology.

Artificial selection has been used for thousands of years in animal and plant breeding to produce pets, farm animals and agriculture crops with desired features.

This has led to the development of many of the animals and plants we now rely on for food or companionship like dairy cattle, rice and Golden Retrievers.

These approaches were even lauded by English naturalist Charles Darwin for their astonishing ability to generate from wolves our domesticated dogs which are as different as Chihuahuas and Great Danes.

Today, advances in genomic approaches have made artificial selection methods considerably more sophisticated than in Darwins day. We can now use genomic information to predict what traits an animal will have with an approach known as genomic selection.

Genomic selection may be a game changer for endangered wildlife because it allows for the development of informed breeding strategies that promote adaptation.

It works by first understanding and identifying what genetic features make members of a species more adapted to an environment or threat than others. This is usually done by exposing individuals in a reference population to the threat (like heat stress or infectious disease) and then measuring their response.

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We then look for genes that are present in individuals that resist and survive the threat. This genetic information can be used to predict which animals in the breeding population are better adapted to survive a given threat based on their own genotype.

Over time, the use of genomic selection as a breeding strategy can increase the average ability of these individuals in the breeding population to survive by promoting adaptation in captivity.

The ability to use this sort of genomic prediction data based on discrete groups of individuals is a major advantage because it means that risky activities, like exposing a population to a disease or other infection as part of a trial, can be performed separately in laboratories away from the critical breeding populations.

Synthetic biology is newer and more controversial than artificial selection. It includes methods like transgenesis and gene editing.

While these methods frequently figure in science fiction and are sometimes feared for their unintended consequences, the real science of synthetic biology is gaining traction in the conservation community due to its many benefits.

Additionally, a recent public opinion survey conducted by the Commonwealth Scientific and Industrial Research Organisation (CSIRO) indicates that the public are moderately-to-strongly supportive of use of synthetic biology approaches for conservation.

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Synthetic biology can be used to introduce lost or novel genes and tweak specific genetic features of an organism without changing other characteristics, which often occurs with less targeted approaches like artificial selection.

Transgenesis does this by incorporating foreign DNA from a different species into the genome. Gene editing is more subtle and works by inducing the organism itself to knock out or replace targeted genes.

American Chestnut trees, corals and black-footed ferrets are just some of the species that synthetic biology methods are currently being trialled to assist with restoration. American Chestnut trees, in particular, are a great success story for the use of synthetic biology for conservation.

This species was driven to virtual extinction in North America after the introduction of the Asian Chestnut Blight fungus in the late 1800s.

Various approaches have been tested to increase resistance to this pathogen with varying degrees of success, but since the tree lacks natural resistance, the most effective approach to date has involved using transgenesis to introduce a new disease-tolerant gene from wheat.

This has produced American Chestnut trees that appear to be blight tolerant. Trial plantings of these trees in American forests may soon start, pending regulatory approval.

Read more

My research group at the University of Melbourne was recently awarded grants from the Australian Research Council (here and here) to test TGI approaches in various Australian frogs vulnerable to extinction.

Many frogs in Australia and globally are threatened by the devastating fungal disease chytridiomycosis. This disease is caused by the introduced fungus Batrachochytrium dendrobatidis and unfortunately few options exist for restoring frogs susceptible to this disease to the wild.

We are working with various institutions including Zoos Victoria and the Taronga Conservation Society to investigate if TGI approaches can be used to increase chytridiomycosis resistance in Australian frogs.

We are currently working on the iconic Southern Corroboree frog (Pseudophryne corroboree) and, in the next few years, we intend to add additional species like the Green and Golden Bell frog (Litoria aurea) and Northern Corroboree frog (Pseudophryne pengilleyi).

Its imperative that we as a community investigate the application of TGI approaches for conservation as in some cases they may be the only way to restore a species in the wild.

Read more

But with this comes the responsibility of the public, government and scientists to not only fund research on TGI, but to also make sure that it is done responsibly with careful consideration to all entities impacted and with proper evaluation of all potential risks.

Since TGI for conservation is a new concept, species modified by TGI should be evaluated to ensure that induced genetic changes increase survival and that the organisms pose no risk to the environment by occupying a different niche or position in the food chain.

Given the scale and seriousness of the challenge in conserving our wildlife, and given the established efficacy of TGI, its an approach that we cant afford to ignore.

The ideas introduced in this article are discussed in more detail in our recent article in the journal Trends in Ecology and Evolution. Dr Koschs co-authors are Anthony W. Waddle, Dr Caitlin A. Cooper, Professor Kyall R. Zenger, Professor Dorian J. Garrick, Associate Professor Lee Berger, and Professor Lee F. Skerratt.

The southern corroboree frog genome is being sequenced for the researchers by the Vertebrate Genomes Project.

Banner: Getty Images

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Using genetics to conserve wildlife - Pursuit

At a Glance

Approximately 1,800 children in the United States die from sudden, unexplained causes each year, most while asleep. When it happens in children under 1 year of age, it's called sudden infant death syndrome (SIDS). In children 1 year of age or older, its called sudden unexplained death in children (SUDC). While SIDS cases outnumber SUDC cases by four to one, research funding and published studies for SIDS have dwarfed that for SUDC.

A research team led by Drs. Richard Tsien and Orrin Devinsky at the NYU Grossman School of Medicine sought to identify genetic mutations that might contribute to SUDC. To do so, they sequenced DNA from 124 SUDC cases and their parents. DNA was extracted from samples collected through the SUDC Registry and Research Collaborative.

NIHs National Institute on Drug Abuse (NIDA) and National Institute of Mental Health (NIMH) supported the work. Results appeared in Proceedings of the National Academy of Sciences on December 28, 2021.

The team first sequenced whole exomes, the 1% of the human genome that codes for proteins. There werent enough subjects to uncover genetic associations in a broad, initial analysis. The researchersthen focused on 137 genes associated with heart or seizure disorders, both of which can trigger sudden death.

They found that in SUDC cases, these genes contained significantly more mutations than would be expected by chance. Most were de novo mutations, meaning that while they were found in the child, they werent found in either parent. A handful of potentially harmful mutations in these genes occurred in parents. In such cases, the mutation also showed up in the offspring 80% of the timeagain, more often than would be expected by chance.

The researchers identified 11 particular mutations that were likely to cause health problems. These mutations were estimated to contributed to death in 9% of cases. Many of the mutations occurred in a cluster of genes that regulate calcium in neurons and heart muscle cells. Calcium changes in these cells control nerve signal transmission and muscle contraction. Mutations in one of the genes, RYR2, have been linked to heart problems. Mutations in another, CACNA1C, have been linked to a rare disorder, called Timothy syndrome, that can affect the heart, limbs, muscle, and brain.

The results suggest that altered calcium signaling may play a significant role in SUDC. They also highlight the importance of de novo mutations for SUDC risk. Studies in larger samples might reveal additional genetic risk factors. Identifying these risk factors is the first step towards developing life-saving medical interventions.

Our study is the largest of its kind to date, the first to prove that there are definite genetic causes of SUDC, and the first to fill in any portion of the risk picture, Tsien says. Along with providing comfort to parents, new findings about genetic changes involved will accumulate with time, reveal the mechanisms responsible, and serve as the basis for new treatment approaches.

by Brian Doctrow, Ph.D.

Funding:NIHs National Institute on Drug Abuse (NIDA) and National Institute of Mental Health (NIMH); SUDC Foundation; Finding a Cure for Epilepsy and Seizures (FACES); Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

Read this article:
Genetics of sudden unexplained death in children - National Institutes of Health

Full-Year 2021 Galafold Revenue of ~$306M, Representing 17% YoY Growth

Expect Double-Digit Growth (15-20%) of 2022 Galafold Revenue with $350M-$365M in Global Sales

U.S. and EU Regulatory Reviews Underway for AT-GAA in Pompe Disease

AT-GAA Global Launch Preparations Accelerating

Cash Flow and Balance Sheet Sufficient to Achieve Self-Sustainability and Profitability by 2023

PHILADELPHIA, Jan. 10, 2022 (GLOBE NEWSWIRE) -- Amicus Therapeutics (Nasdaq: FOLD), a patient-dedicated global biotechnology company focused on developing and commercializing novel medicines for rare diseases, today provided its preliminary and unaudited 2021 revenue, corporate updates, and full-year 2022 outlook and revenue guidance.

Corporate Highlights:

Global revenue for Galafold (migalastat) in 2021 reached $306 million driven by strong new patient accruals and sustained patient adherence, representing a year-over-year increase of 17%.

AT-GAA regulatory reviews are underway: In the U.S., the Food and Drug Administration (FDA) accepted for review the Biologics License Application (BLA) for cipaglucosidase alfa and the New Drug Application (NDA) for miglustat, the two components of AT-GAA. The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of May 29, 2022 for the NDA and July 29, 2022 for the BLA. In the EU, the Marketing Authorization Applications (MAA) were submitted and validated in the fourth quarter by the European Medicines Agency (EMA).

AT-GAA launch preparations are accelerating: Development of global launch plans, targeted investments in additional personnel, and launch inventory are fully underway as company believes AT-GAA can rapidly become the new standard of care treatment regimen for people living with Pompe disease.

Pipeline of next generation genetic medicines to advance through both internal efforts and creation of R&D focused new company, Caritas Therapeutics.

Cash Flow and Balance Sheet sufficient to achieve self-sustainability and profitability in 2023. Through careful management of expenses, the Company is on the path to achieve self-sustainability and profitability in 2023 as it executes on the global Galafold expansion and prepares for AT-GAA global launch.

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John F. Crowley, Chairman and Chief Executive Officer of Amicus Therapeutics, Inc., stated, In 2021, Amicus made great strides for people worldwide living with rare diseases through the broad execution of our annual strategic priorities. Despite the resurgence of COVID with Delta and Omicron variants, the Galafold business remains very strong, and we delivered on our full year revenue guidance and expect robust growth this year driven by strong adoption across the globe for our Fabry disease precision medicine. We are underway with the global regulatory reviews and launch preparations for AT-GAA in Pompe disease with high expectations that this novel medicine has the potential to become the new standard of care in Pompe disease treatment and the potential to address unmet needs for thousands of Pompe patients in the years ahead. We see further opportunity ahead to impact the lives of those living with rare disease through our genetic medicine business and capabilities. Together, Amicus is in a stronger position than ever and we remain steadfast on our mission of transforming the lives of people living with rare, life-threatening conditions and creating significant value for our shareholders.

Bradley Campbell, President and Chief Operating Officer of Amicus Therapeutics, Inc., stated, We are looking ahead to transforming Amicus into a leading global rare disease biotechnology company led by two innovative therapies that we believe meaningfully impact the lives of people living with Fabry and Pompe disease. This year we will be focused on continuing to bring Galafold to patients around the world and delivering on the anticipated approval and launch of AT-GAA.

Amicus is focused on the following five key strategic priorities in 2022:

Continued double-digit Galafold growth (15-20%) with revenue of $350M to $365M

Secure FDA approval and positive CHMP opinion for AT-GAA

Initiate successful, rapid launch in the U.S. for AT-GAA

Advance best-in-class next generation genetic medicines and capabilities

Maintain strong financial position on path to profitability

Mr. Crowley and Mr. Campbell will discuss the Amicus corporate objectives and key milestones in a presentation at the 40th Annual J.P. Morgan Healthcare Conference on Wednesday, January 12, 2022, at 3:45 p.m. ET. A live webcast of the presentation can be accessed through the Investors section of the Amicus Therapeutics corporate website at http://ir.amicusrx.com/events.cfm, and will be archived for 90 days.

Full-Year 2021 Revenue Summary and 2022 Revenue Guidance

Global revenue for Galafold in full-year 2021 was approximately $306 million, preliminary and unaudited, representing a year-over-year increase of 17% from total revenue of $260.9 million in 2020. Full-year revenue benefited from a positive currency impact of approximately $7 million. Fourth quarter Galafold revenue was approximately $84 million, preliminary and unaudited.

For the full-year 2022, the Company anticipates total Galafold revenue of $350 million to $365 million. Double-digit revenue growth (15-20%) in 2022 is expected to be driven by continued underlying demand from both switch and nave patients, geographic expansion, the continued diagnosis of new Fabry patients and commercial execution across all major markets, including the U.S., EU, U.K., and Japan.

The current cash position is sufficient to achieve self-sustainability and profitability in 2023.

Updates and Anticipated Milestones by Program

Galafold (migalastat) Oral Precision Medicine for Fabry Disease

Sustain double-digit revenue growth in 2022 of $350 million to $365 million

Continue geographic expansion

Registry and other Phase 4 studies ongoing

AT-GAA for Pompe Disease

U.S. Prescription Drug User Fee Act (PDUFA) action date of May 29, 2022 for the NDA and July 29, 2022 for the BLA

EU Committee for Medicinal Products for Human Use (CHMP) opinion expected in late 2022

Continue to broaden access through early access plans in the U.K., Germany, Japan, and other countries

Ongoing supportive studies, including pediatric and extension studies

Gene Therapy Pipeline

Advance IND-enabling studies, manufacturing activities, and regulatory activities for the Fabry disease gene therapy program towards an anticipated IND in 2023

Progress preclinical studies, manufacturing activities, and regulatory activities for the Pompe disease gene therapy program

Discontinue CLN6 Batten disease gene therapy program following review of long-term extension study data. It was recently determined that any initial stabilization of disease progression at the two-year time point was not maintained through the long-term extension study. Amicus plans to further analyze and share the Phase 1/2 data with key stakeholders in the CLN6 Batten disease community and work with the community to support continued research efforts to find better treatments and cures which are so desperately and urgently needed

Advance CLN3 Batten disease program with the higher dose, different promoter, and intra-cisterna magna (ICM) route of delivery pending further Phase 1/2 clinical data and pre-clinical data expected in 2022. These data will inform timeline for commencement of any pivotal clinical study

About GalafoldGalafold (migalastat) 123 mg capsules is an oral pharmacological chaperone of alpha-galactosidase A (alpha-Gal A) for the treatment of Fabry disease in adults who have amenable galactosidase alpha gene (GLA) variants. In these patients, Galafold works by stabilizing the bodys own dysfunctional enzyme so that it can clear the accumulation of disease substrate. Globally, Amicus Therapeutics estimates that approximately 35 to 50 percent of Fabry patients may have amenable GLA variants, though amenability rates within this range vary by geography. Galafold is approved in over 40 countries around the world, including the U.S., EU, U.K., Japan and others.

U.S. INDICATIONS AND USAGEGalafold is indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data.

This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

U.S. IMPORTANT SAFETY INFORMATION

ADVERSE REACTIONSThe most common adverse reactions reported with Galafold (10%) were headache, nasopharyngitis, urinary tract infection, nausea and pyrexia.

USE IN SPECIFIC POPULATIONSThere is insufficient clinical data on Galafold use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Advise women of the potential risk to a fetus.

It is not known if Galafold is present in human milk. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Galafold and any potential adverse effects on the breastfed child from Galafold or from the underlying maternal condition.

Galafold is not recommended for use in patients with severe renal impairment or end-stage renal disease requiring dialysis.

The safety and effectiveness of Galafold have not been established in pediatric patients.

To report Suspected Adverse Reactions, contact Amicus Therapeutics at 1-877-4AMICUS or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

For additional information about Galafold, including the full U.S. Prescribing Information, please visit https://www.amicusrx.com/pi/Galafold.pdf.

EU Important Safety InformationTreatment with Galafold should be initiated and supervised by specialists experienced in the diagnosis and treatment of Fabry disease. Galafold is not recommended for use in patients with a nonamenable mutation.

Galafold is not intended for concomitant use with enzyme replacement therapy.

Galafold is not recommended for use in patients with Fabry disease who have severe renal impairment (<30 mL/min/1.73 m2). The safety and efficacy of Galafold in children less than 12 years of age have not yet been established. No data are available.

No dosage adjustments are required in patients with hepatic impairment or in the elderly population.

There is very limited experience with the use of this medicine in pregnant women. If you are pregnant, think you may be pregnant, or are planning to have a baby, do not take this medicine until you have checked with your doctor, pharmacist, or nurse.

While taking Galafold, effective birth control should be used. It is not known whether Galafold is excreted in human milk.

Contraindications to Galafold include hypersensitivity to the active substance or to any of the excipients listed in the PRESCRIBING INFORMATION.

Galafold 123 mg capsules are not for children (12 years) weighing less than 45 kg.

It is advised to periodically monitor renal function, echocardiographic parameters and biochemical markers (every 6 months) in patients initiated on Galafold or switched to Galafold.

OVERDOSE: General medical care is recommended in the case of Galafold overdose.

The most common adverse reaction reported was headache, which was experienced by approximately 10% of patients who received Galafold. For a complete list of adverse reactions, please review the SUMMARY OF PRODUCT CHARACTERISTICS.

Call your doctor for medical advice about side effects.

For further important safety information for Galafold, including posology and method of administration, special warnings, drug interactions and adverse drug reactions, please see the European SmPC for Galafold available from the EMA website at http://www.ema.europa.eu.

About Fabry Disease

Fabry disease is an inherited lysosomal disorder caused by deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A), which results from mutations in the GLA gene. The primary biological function of alpha-Gal A is to degrade specific lipids in lysosomes, including globotriaosylceramide (referred to here as GL-3 and also known as Gb3). Lipids that can be degraded by the action of alpha-Gal A are called "substrates" of the enzyme. Reduced or absent levels of alpha-Gal A activity lead to the accumulation of GL-3 in the affected tissues, including heart, kidneys, and skin. Accumulation of GL-3 and progressive deterioration of organ function is believed to lead to the morbidity and mortality of Fabry disease. The symptoms can be severe, differ from person to person, and begin at an early age.

About Amicus Therapeutics

Amicus Therapeutics (Nasdaq: FOLD) is a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel high-quality medicines for people living with rare metabolic diseases. With extraordinary patient focus, Amicus Therapeutics is committed to advancing and expanding a robust pipeline of cutting-edge, first- or best-in-class medicines for rare metabolic diseases. For more information please visit the companys website at http://www.amicusrx.com, and follow us on Twitter and LinkedIn.

Forward Looking Statement

This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 relating to preclinical and clinical development of our product candidates, the timing and reporting of results from preclinical studies and clinical trials, the prospects and timing of the potential regulatory approval of our product candidates, commercialization plans, manufacturing and supply plans, financing plans, and the projected revenues and cash position for the Company. The inclusion of forward-looking statements should not be regarded as a representation by us that any of our plans will be achieved. Any or all of the forward-looking statements in this press release may turn out to be wrong and can be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. For example, with respect to statements regarding the goals, progress, timing, and outcomes of discussions with regulatory authorities, and in particular the potential goals, progress, timing, and results of preclinical studies and clinical trials, including as they are impacted by COVID-19 related disruption, are based on current information. The potential impact on operations from the COVID-19 pandemic is inherently unknown and cannot be predicted with confidence and may cause actual results and performance to differ materially from the statements in this release, including without limitation, because of the impact on general political and economic conditions, including as a result of efforts by governmental authorities to mitigate COVID-19, such as travel bans, shelter in place orders and third-party business closures and resource allocations, manufacturing and supply chain disruptions and limitations on patient access to commercial or clinical product. In addition to the impact of the COVID-19 pandemic, actual results may differ materially from those set forth in this release due to the risks and uncertainties inherent in our business, including, without limitation: the potential that results of clinical or preclinical studies indicate that the product candidates are unsafe or ineffective; the potential that it may be difficult to enroll patients in our clinical trials; the potential that regulatory authorities, including the FDA, EMA, and PMDA, may not grant or may delay approval for our product candidates; the potential that we may not be successful in commercializing Galafold in Europe, Japan, the US and other geographies or our other product candidates if and when approved; the potential that preclinical and clinical studies could be delayed because we identify serious side effects or other safety issues; the potential that we may not be able to manufacture or supply sufficient clinical or commercial products; and the potential that we will need additional funding to complete all of our studies and manufacturing. Further, the results of earlier preclinical studies and/or clinical trials may not be predictive of future results. Statements regarding corporate financial guidance and financial goals and the attainment of such goals. With respect to statements regarding projections of the Company's revenue and cash position, actual results may differ based on market factors and the Company's ability to execute its operational and budget plans. In addition, all forward-looking statements are subject to other risks detailed in our Annual Report on Form 10-K for the year ended December 31, 2020 and the Quarterly Report filed on Form 10-Q for the quarter ended September 30, 2021. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, and we undertake no obligation to revise or update this news release to reflect events or circumstances after the date hereof.

CONTACT:

Investors: Amicus Therapeutics Andrew FaughnanExecutive Director, Investor Relationsafaughnan@amicusrx.com(609) 662-3809

Media: Amicus Therapeutics Diana Moore Head of Global Corporate Communicationsdmoore@amicusrx.com(609) 662-5079

FOLDG

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Amicus Therapeutics Reports Preliminary 2021 Revenue and Provides 2022 Strategic Outlook and Revenue Guidance - Yahoo Finance

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Maze Therapeutics, a company translating genetic insights into new precision medicines, today announced a $190 million financing led by Matrix Capital Management with participation from General Catalyst, a16z Bio+Health, Woodline Partners, Casdin Capital, City Hill Ventures, Foresite Capital, Driehaus Capital Management, Moore Strategic Ventures, Terra Magnum Capital Partners, NS Investments and several others. Maze was launched in 2019 with a financing led by Third Rock Ventures and ARCH Venture Partners, with participation from GV, Foresite Capital, Casdin Capital, Alexandria Venture Investments and other undisclosed investors and has since generated nine programs and two joint-ventures. In conjunction with the financing, Maze also announced that Matrix Capital Managements Andy Tran has joined the companys board of directors.

Over the past year, Maze has generated data across multiple disease areas and modalities, said Jason Coloma, Ph.D., president and chief executive officer of Maze. I am confident that Maze has emerged at precisely the right moment with the right people to execute on an ambitious and important mission, and I am proud of our team for the progress made in our pipeline to date. As we transition to a clinical-stage company, we believe this financing provides important resources to advance our pipeline and to uncover new genetic associations to develop precision medicines for patients with genetically defined diseases.

We think Mazes unique approach that fuses deep human genetics with a platform that can deliver end-to-end computational chemistry informed drug discovery has the potential to generate a continuous stream of precision therapies in complex disease areas that have long been underserved and lack meaningful treatment options, said Andy Tran, investor at Matrix Capital Management and incoming Maze board director. We have been impressed by the rapid progress from idea to program this world-class team of drug hunters and computational biologists has made and look forward to supporting the company in this next wave of growth.

Proceeds from the financing will be used to support advancement of the companys nine precision medicines programs for both rare and common genetically defined diseases with high unmet need, including its three most advanced programs, MZE001 for the treatment of Pompe disease, its APOL1 program for the treatment of chronic kidney disease and its ATXN2 program for the treatment of amyotrophic lateral sclerosis (ALS). The company expects MZE001 to enter the clinic in the first half of 2022. Proceeds will also be used to further expand Maze Compass, the companys purpose-built, end-to-end platform that seeks to take advantage of scientific advancements in genetics, genomics and data science to expedite drug discovery by focusing on variant functionalization to develop new small molecule and biologic therapies for patients with genetically based disorders.

Charles Homcy, M.D., chairman of the board and partner at Third Rock Ventures, commented, The foundational vision of Maze was focused on applying learnings from the evolving landscape of genetic insights and the role they play in disease and translating that knowledge into new medicines where other approaches have fallen short. With the combination of its Compass platform, an exceptional team and this latest financing, I believe Maze is well-positioned to realize the potential of its vision and the true impact we may be able to make for many patients.

About Maze Therapeutics

Maze Therapeutics is a biopharmaceutical company applying advanced data science methods in tandem with a robust suite of research and development capabilities to advance a pipeline of novel precision medicines for patients with genetically defined diseases. Maze has developed the Maze CompassTM platform, a proprietary, purpose-built platform that combines human genetic data, functional genomic tools and data science technology to map novel connections between known genes and their influence on susceptibility, timing of onset and rate of disease progression. Using Compass, Maze is building a broad portfolio, including wholly owned programs targeting Pompe disease, chronic kidney disease and amyotrophic lateral sclerosis, as well as partnered programs in cardiovascular and ophthalmic diseases. Maze is based in South San Francisco. For more information, please visit mazetx.com, or follow us on LinkedIn and Twitter.

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Maze Therapeutics Announces $190 Million Financing to Support the Advancement of Nine Precision Medicine Programs and Compass Platform for Genetically...

I said, I am an RNA scientist. I can do anything with RNA, Dr. Karik recalled telling Dr. Weissman. He asked her: Could you make an H.I.V. vaccine?

Oh yeah, oh yeah, I can do it, Dr. Karik said.

Up to that point, commercial vaccines had carried modified viruses or pieces of them into the body to train the immune system to attack invading microbes. An mRNA vaccine would instead carry instructions encoded in mRNA that would allow the bodys cells to pump out their own viral proteins. This approach, Dr. Weissman thought, would better mimic a real infection and prompt a more robust immune response than traditional vaccines did.

It was a fringe idea that few scientists thought would work. A molecule as fragile as mRNA seemed an unlikely vaccine candidate. Grant reviewers were not impressed, either. His lab had to run on seed money that the university gives new faculty members to get started.

By that time, it was easy to synthesize mRNA in the lab to encode any protein. Drs. Weissman and Karik inserted mRNA molecules into human cells growing in petri dishes and, as expected, the mRNA instructed the cells to make specific proteins. But when they injected mRNA into mice, the animals got sick.

Their fur got ruffled, they hunched up, they stopped eating, they stopped running, Dr. Weissman said. Nobody knew why.

For seven years, the pair studied the workings of mRNA. Countless experiments failed. They wandered down one blind alley after another. Their problem was that the immune system sees mRNA as a piece of an invading pathogen and attacks it, making the animals sick while destroying the mRNA.

Eventually, they solved the mystery. The researchers discovered that cells protect their own mRNA with a specific chemical modification. So the scientists tried making the same change to mRNA made in the lab before injecting it into cells. It worked: The mRNA was taken up by cells without provoking an immune response.

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How The mRNA Vaccines Were Made: Halting Progress and Happy Accidents - The New York Times

BETHESDA, Md., Jan.12, 2022 /PRNewswire/ --The ACMG Annual Clinical Genetics Meetingwill be a hybrid event in 2022 with the options to attend in person in Nashville or online. This meeting continues to provide groundbreaking research and the latest advances in medical genetics, genomics and personalized medicine. The 2022 ACMG Annual Clinical Genetics Meeting will offer media a firsthand look at what is shaping the future of genetics and genomics in medicine and will offer a variety of engaging and interactive educational formats and types of sessionsfrom Scientific Sessions and Workshops to TED-Style Talks, Case-based Sessions, Platform Presentations and Short Courses.

Interview those at the forefront in medical genetics and genomics, connect with new sources, and get story ideas on the clinical practice of genetics and genomics in healthcare today and for the future. Learn how genetics and genomics research is being integrated and applied in medical practice. Topics include artificial intelligence in genetics, gene editing, cancer genetics, direct-to-consumer genetic testing, exome sequencing, pre- and perinatal genetics, the importance of diversity, equity and inclusion in the study of genetics, biochemical/metabolic genetics, genetic counseling, health services and implementation, legal and ethical issues, therapeutics and more.

Credentialed media representatives on assignment are invited to cover the ACMG Annual Meeting Hybrid Event on a complimentary basis. Contact Reymar Santos at [emailprotected]for the Press Registration Invitation Code, which will be needed to register at http://www.acmgmeeting.net.

Abstracts will be available online in February. All attendees will have access to session recordings until April 30.

A few 2022 ACMG Annual Meeting highlights include:

Program Highlights:

Two Short Courses Available Starting on Tuesday, March 22:

Cutting-Edge Scientific Concurrent Sessions:

Social Media for the 2022 ACMG Meeting: As the ACMG Annual Meeting approaches, journalists can stay up to date on new sessions and information by following the ACMG social media pages on Facebook,Twitterand Instagramand by usingthe hashtag #ACMGMtg22 for meeting-related tweets and posts.

The ACMG Annual Meeting website has extensive information at http://www.acmgmeeting.netand will be updated as new information becomes available. All plenaries plus one session per time block are currently planned for streaming.

About the American College of Medical Genetics and Genomics (ACMG) and ACMG Foundation

Founded in 1991, the American College of Medical Genetics and Genomics (ACMG) is the only nationally recognized medical professional organization solely dedicated to improving health through the practice of medical genetics and genomics, and the only medical specialty society in the US that represents the full spectrum of medical genetics disciplines in a single organization. The ACMG is the largest membership organization specifically for medical geneticists, providing education, resources and a voice for more than 2,400 clinical and laboratory geneticists, genetic counselors and other healthcare professionals, nearly 80% of whom are board certified in the medical genetics specialties. ACMG's mission is to improve health through the clinical and laboratory practice of medical genetics as well as through advocacy, education and clinical research, and to guide the safe and effective integration of genetics and genomics into all of medicine and healthcare, resulting in improved personal and public health. Four overarching strategies guide ACMG's work: 1) to reinforce and expand ACMG's position as the leader and prominent authority in the field of medical genetics and genomics, including clinical research, while educating the medical community on the significant role that genetics and genomics will continue to play in understanding, preventing, treating and curing disease; 2) to secure and expand the professional workforce for medical genetics and genomics; 3) to advocate for the specialty; and 4) to provide best-in-class education to members and nonmembers. Genetics in Medicine, published monthly, is the official ACMG journal. ACMG's website (www.acmg.net) offers resources including policy statements, practice guidelines, educational programs and a 'Find a Genetic Service' tool. The educational and public health programs of the ACMG are dependent upon charitable gifts from corporations, foundations and individuals through the ACMG Foundation for Genetic and Genomic Medicine.

Kathy Moran, MBA[emailprotected]

SOURCE American College of Medical Genetics and Genomics

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Press Registration Is Now Open for the 2022 ACMG Annual Clinical Genetics Meeting - PRNewswire

Introduction

Long QT syndrome (LQTS) is defined by a prolonged QT interval accompanied by morphological abnormalities in the T and/or U waves on the electrocardiograph (ECG).1 The primary clinical symptom of LQTS is syncope produced by ventricular arrhythmias.24 The clinical diagnosis of LQTS is based on a combination of the patients medical and family history, as well as the 12-lead ECG.5 According to the guidelines, LQTS diagnosis can be made in case the QTc is more than 460ms, and the patient presents some antecedents, most notably a family history of SCD and unexplained syncope.6

LQTS can be classified into two types based on its etiology: congenital LQTS (cLQTS) and acquired LQTS (aLQTS). While the former is a relatively rare genetic cardiovascular disease with a low incidence rate (1/2000-1/3000),7 the latter is frequently subsequent to electrolyte disorders, cardiomyopathy, cerebrovascular accidents, and autonomic dysfunction.

The pathogenesis of cLQTS is related to the mutation of genes encoding for ion channels, such as KCNH2,3,8 KCNQ1,2,9 TRPM4,1012 and so on, and causing ion channel dysfunction with reduced repolarization ion flow and/or increased delocalization ion flow, which in turn leads to prolonged repolarization. Among ion channel genes, mutations in KCNQ1 and KCNH2, which encode voltage-gated K+ channels involved in cardiac action potential (AP) repolarization are most common,10 followed by mutations in SCN5A which encode voltage-gated Na (1.78%), while mutations in other genes including TRPM4 are rare (below 1% of LQTS).11 Dr. Hof and colleagues were the first to hypothesize that TRPM4 mutations cause long QT syndrome, and they detected four TRPM4 variants, including c.1321 G >A, c.1495 C >T, c.1496 G >C, and c.2531 G >A, with no changes in the key LQTS genes.11

Herein, we reported a Chinese proband with cLQTS with a new mutation (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133) in the TRPM4 with the hope that this report may be helpful in future genetic studies and prospective, genetically informed research.

A 75-year-old male was implanted with a permanent pacemaker 18 years ago due to a local diagnosis of bradycardia characterized by recurrent syncope since the age of 20, yet postoperative syncope continued to occur. Syncope occurred again a day before admission, and then he was taken to our hospital. Electrocardiography (ECG) at disease onset indicated sinus bradycardia, anterior wall T wave changes with visible u waves (Figure 1).

Figure 1 The admission ECG showed sinus bradycardia with QTc interval 432ms and U wave.

On admission, the following vital signs were recorded: blood pressure of 135/88mmHg, pulse rate of 59 beats per minute, the body temperature of 36.4C, and breathing rate of 18 beats per minute. Physical examination revealed no evidence of heart failure or pathological nervous system features.

After admission, repeated electrocardiograms suggested prolonged QT intervals, sinus bradycardia, and T wave changes (Figure 2). Ambulatory ECG also showed sinus bradycardia (mean heart rate 59 beats), prolonged QT interval (540ms), and torsade de pointes (Figure 3). Whats more, the electrodes on the patients pacemaker were discovered to be depleted for nearly five years. Laboratory data showed a slightly elevated level of troponin, as well as N-terminal-pro-brain natriuretic peptide, while other laboratory indexes including hepatic and renal function, electrolytes, coagulation, and inflammatory indexes were normal. We also performed a cranial MRI on this patient, and no neurological lesion was found that could cause syncope. Echocardiography indicated no abnormalities in cardiac structure, and the left ventricular ejection fraction was 61%. Moreover, selective coronary angiography was performed, indicating that the patient has no apparent pathological stenosis in the coronary arteries.

Figure 2 (AC) During the hospitalization, the ECG showed the dynamic changes of T wave; the longest QTc interval was 540ms.

Figure 3 Electrocardiogram monitoring shows torsion de pointes tachycardia.

According to the above results and the diagnostic criteria of LQTS, a highly suspected diagnosis of LQTS was finally made (Rating 6.5 out of 5).1,13,14

Then the etiology of LQTS was further explored. For no acquired LQTS associated risk factors such as electrolyte disorders, cardiomyopathy, cerebrovascular accidents, and autonomic dysfunction were found in the patients previous medical history and related examinations after admission, we are suspicious of the patients Genetics of LQTS.

After obtaining the informed consent, we conducted whole-exome sequencing (WES) on the patient and his family to confirm our diagnosis. Gene testing revealed that the patient carried a TRPM4 heterozygous shift mutation (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133). Moreover, WES analysis of his family members revealed that his sister carried the same TRPM4 mutation as the patient (Figure 4), but his two brothers and son did not. Regrettably, the probands parents have all died, and hence their genes have not been obtained.

Figure 4 The results of genetic testing showed the proband and his sister carried a TRPM4 heterozygous shift mutation (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133) (A), while his two brothers and son did not (B).

Because of the high risk of sudden cardiac death, we recommend implanting a cardioverter defibrillator (ICD) for the patient. Due to economic reasons, the patient refused. Due to the patients strong preference for cautious treatment, we administered Shengsong Yangxin Capsule as a placebo.

cLQTS is a rare cardiac disorder inherited in an autosomal trait, with an estimated incidence of 1:20001:3000.7 It is accepted that cLQTS is a rare ion channelopathy, and a host of genes were described to be responsible for LQTS. So far, 15 genes with more than 7000 mutations have been considered to be associated with cLQTS.15 Among the six genes encode for a pore-forming ion channel, while others encode for regulatory subunits or proteins. Mutations in KCNQ1 (3035%) and KCNH2 (2530%) encoding voltage-gated K+ channels involved in cardiac action potential (AP) repolarization are the most common among ion channel genes,10,14 followed by mutations in SCN5A, which encode voltage-gated Na+ (1.78%).11,14 In comparison, mutations in other genes, including TRPM4 are rare (below 1% of LQTS).11,12,14

As far as the pathology of LQTS, it is generally known that QT duration depends on both ventricular AP duration and AP propagation within the ventricle and ion channel dysfunction with reduced repolarization ion flow and/or increased delocalization ion flow leads to prolonged repolarization. According to a sack of animal experiments on TRPM4, TRPM4 affects cardiac electrophysiological activity through nonselective cation permeability, which leads to cLQTS.11 Unfortunately, additional research is required to decipher the biological mechanism underlying TRPM4-induced loss of function of nonselective cation permeability.

Above all, gene test counts for cLQTS. The importance of gene detection for cLQTS lies in exploring its pathogenic mechanism and its treatment, for the drugs targeted specific ion channels can be used with exerting maximal effects.

In our case, a new mutation site on TRPM4 (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133) was discovered through whole-exon detection, which can provide a brand-new direction for gene screening of patients with cLQTS and further complements its diagnostic criteria. As for the detail of gene tests, we used PolyPhen2 to predict whether a new mutation is damaging to the resultant protein function. And then, according to the relevant literature, we did consider that TRPM4 is as same amino acid change as a previously established pathogenic variant regardless of nucleotide change after searching the OMIM database. But the absence of the literature for molecular pathology makes us failure to achieve the information of damaged protein. At last, combined clinical history, ECG, and the results of gene test, it was suspected that TRPM4 mutation (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133) was the pathogenic variant.

In the treatment of cLQTS, beta-blockers effectively prevent cardiovascular disease and ventricular arrhythmia, and ICD implantation is regarded as the ultimate therapy.16 Because of the high risk of sudden cardiac death, we recommend implanting a cardioverter defibrillator (ICD) for the patient. Due to economic reasons, the patient refused, and we administered a placebo.

The incidence of cLQTS is very low, with the incidence of LQTS caused by TRPM4 being even lower, leading to less research on the gene TRPM4. Therefore, we reported a new mutation in TRPM4 (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133) to provide more evidence for gene screening, to improve the detection rate of healthy gene carriers or patients in the early incubation stage, thereby providing further complements to the clinical data of the study about TRPM4. Notwithstanding its limitation such as lack of this patients past clinical data that can help to compare the symptom before and after the permanent pacemaker implantation, detailed information of the pedigree of this patients parents and so on, this report does hopefully serve as useful feedback information for genetic pathogenesis of cLQTS caused by TRPM4 variants.

cLQTS, congenital long QT syndrome; LQTS, long QT syndrome; ECG, electrocardiograph; AP, action potential; ICD, implanting cardioverter defibrillator; WES, whole-exome sequencing; TRPM4, transient receptor potential melastatin 4; aLQTS, acquired LQTS.

All relevant data supporting the conclusions of this article are included within the article.

The need for institutional ethics approval for this case report was waived. Written informed consent was obtained from the patient for publication of this case report and accompanying images.

The patient has provided informed consent for the publication of the case. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Dr. Rui Huang and Dr. Yinhua Luo are co-first authors for this study.

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

This work was supported in part by the National Natural Science Foundation of China (82160072) and the Science and Technology Support Project of Enshi Science and Technology Bureau (D20210024).

The authors declare that they have no conflicts of interest.

1. Vohra J. The long QT syndrome. Heart Lung Circ. 2007;16(Suppl 3):S5S12. doi:10.1016/j.hlc.2007.05.008

2. Beiyin G, Tingliang L, Lei Y, et al. Head-up tilt test induces T-wave alternans in long QT syndrome with KCNQ1 gene mutation: case report CARE-compliant article. Medicine. 2020;99(20):e19818.

3. Henk-Jan B, Lucia B. Orgasm induced torsades de pointes in a patient with a novel mutation with long-QT syndrome type 2: a case report. Eur Heart J Case Rep. 2018;2(2):yty062.

4. Joel G, Kinsley H, Amanda W, et al. Recurrent torsades with refractory QT prolongation in a 54-year-old man. Am J Case Rep. 2018;19:1515.

5. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10(12):19321963. doi:10.1016/j.hrthm.2013.05.014

6. Priori SG, Blomstrm-Lundqvist C, Mazzanti A, et al. [2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death]. Kardiol Pol. 2015;73(10):795900. Croatian. doi:10.5603/KP.2015.0190

7. Zumhagen S, Stallmeyer B, Friedrich C, et al. Inherited long QT syndrome: clinical manifestation, genetic diagnostics, and therapy. Herzschrittmacherther Elektrophysiol. 2012;23(3):211219. doi:10.1007/s00399-012-0232-8

8. Du F, Wang G, Wang D, et al. Targeted next generation sequencing revealed a novel deletion-frameshift mutation of KCNH2 gene in a Chinese Han family with long QT syndrome: a case report and review of Chinese cases. Medicine. 2020;99(16):e19749. doi:10.1097/MD.0000000000019749

9. Motoi N, Marehiko U, Ryota E, et al. A novel KCNQ1 nonsense variant in the isoform-specific first exon causes both jervell and Lange-Nielsen syndrome 1 and long QT syndrome 1: a case report. BMC Med Genet. 2017;18(1):16.

10. Amin AS, Pinto YM, Wilde AA. Long QT syndrome: beyond the causal mutation. J Physiol. 2013;591(17):41254139. doi:10.1113/jphysiol.2013.254920

11. Hof T, Liu H, Sall L, et al. TRPM4 non-selective cation channel variants in long QT syndrome. BMC Med Genet. 2017;18(1):31. doi:10.1186/s12881-017-0397-4

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13. Hayashi K, Konno T, Fujino N, et al. Impact of updated diagnostic criteria for long QT syndrome on clinical detection of diseased patients: results from a study of patients carrying gene mutations. JACC Clin Electrophysiol. 2016;2(3):279287. doi:10.1016/j.jacep.2016.01.003

14. Neira V, Enriquez A, Simpson C, et al. Update on long QT syndrome. J Cardiovasc Electrophysiol. 2019;30(12):30683078. doi:10.1111/jce.14227

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16. Betge S, Schulze-Bahr E, Fitzek C, et al. [Long QT syndrome causing grand mal epilepsy: case report, pedigree, therapeutic options, and review of the literature]. Nervenarzt. 2006;77(10):12101217. German. doi:10.1007/s00115-006-2118-7

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A Novel Mutation in the TRPM4 Gene | RRCC - Dove Medical Press

Yang Guo,1 4 Bobin Ning,5 Qunhui Zhang,1 4 Jing Ma,4 Linlin Zhao,1 4 QiQin Lu,1 4 Dejun Zhang1,4

1Research Center for High Altitude Medicine, Medical College of Qinghai University, Xining, 810001, Peoples Republic of China; 2Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province, Medical College of Qinghai University, Xining, 810001, Peoples Republic of China; 3Qinghai-Utah Joint Research Key Lab for High Altitude Medicine, Medical College of Qinghai University, Xining, 810001, Peoples Republic of China; 4Department of Eco-Environmental Engineering, Qinghai University, Xining, 810016, Peoples Republic of China; 5Department of Medicine, The General Hospital of the Peoples Liberation Army, Beijing, 100038, Peoples Republic of China

Correspondence: Dejun ZhangDepartment of Eco-Environmental Engineering, Qinghai University, Qinghai, 810016, Peoples Republic of ChinaEmail [emailprotected]

Purpose: The objective of this study was to identify the potential regulatory mechanisms, diagnostic biomarkers, and therapeutic drugs for heart failure (HF).Methods: Differentially expressed genes (DEGs) between HF and non-failing donors were screened from the GSE57345, GSE5406, and GSE3586 datasets. Database for Annotation Visualization and Integrated Discovery and Metascape were used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses respectively. The GSE57345 dataset was used for weighted gene co-expression network analysis (WGCNA). The intersecting hub genes from the DEGs and WGCNA were identified and verified with the GSE5406 and GSE3586 datasets. The diagnostic value of the hub genes was calculated through receiver operating characteristic analysis and net reclassification index (NRI). Gene set enrichment analysis (GSEA) was used to filter out the signaling pathways associated with the hub genes. SYBYL 2.1 was used for molecular docking of hub targets and potential HF drugs obtained from the connection map.Results: Functional annotation of the DEGs showed enrichment of negative regulation of angiogenesis, endoplasmic reticulum stress response, and heart development. PTN, LUM, ISLR, and ASPN were identified as the hub genes of HF. GSEA showed that the key genes were related to the transforming growth factor- (TGF-) and Wnt signaling pathways. Sirolimus, LY-294002, and wortmannin have been confirmed as potential drugs for HF.Conclusion: We identified new hub genes and candidate therapeutic drugs for HF, which are potential diagnostic, therapeutic and prognostic targets and warrant further investigation.

Keywords: differentially expressed genes, weighted gene co-expression network analysis, diagnostic biomarkers, therapeutic drugs, heart failure

HF is a clinical syndrome characterized by congestion of the lungs and vena cava, leading to abnormal heart structure or function, which is the final stage of the development of heart disease.1 Approximately 40 million people worldwide suffer from HF, and the incidence rates are steadily rising.2 Despite significant progress in the HF management in recent decades, the treatment options are mainly palliative rather than curative.3 Given the complex pathogenesis of HF, it is essential to elucidate the underlying molecular mechanisms in order to identify potential therapeutic targets and prognostic markers.

Bioinformatics is a high-throughput technique that can screen multiple databases to identify the potential pathological biomarkers of various diseases.4 Weighted gene co-expression network analysis (WGCNA) is a systems biology application that mines the genetic interaction networks to construct highly coordinated gene modules.4 WGCNA has been widely used for detecting disease biomarkers, and elucidating biological mechanisms and drug interactions.57 Although biomarkers of HF have been identified, but due to heterogeneity of HF and its complicated pathophysiological manifestations, a single gene cannot accurately predict the characteristics of HF.8,9

In this study, the differentially expressed genes (DEGs) between HF patients and non-failing donors (NFD) were screened from multiple GEO datasets and functionally annotated. The hub genes were then screened through the degree of connectivity in the PPI network, and used to build a co-expression network with WGCNA. The intersecting hub genes between DEGs and WGCNA were identified and validated in other human HF datasets. Gene set enrichment analysis (GSEA) was used to discover the signaling pathways associated with these hub genes. Finally, the potential HF drugs were predicted through the Connectivity Map (cMap) database, and molecular docking between the drug candidates and hub genes was simulated using SYBYL 2.1 software.

We conducted a bioinformatics analysis using DEGS and WGCNA to further investigate the occurrence and development of HF and identify potential therapeutic drugs for biomarkers of HF.

The study design is outlined in Figure 1. We searched the GEO database and included data on human heart tissue samples in this study. The mRNA expression profiles from HF and NFD samples were downloaded from the GSE57345, GSE5406 and GSE3586 datasets of the GEO database (http://www.ncbi.nlm.nih.gov/geo/). The subjects included in our study suffered from heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Among them were 96 patients with ischemic heart disease, 84 patients with dilated cardiomyopathy (CMP), and 139 non-heart failure samples from GSE57345.10 The GSE5406 dataset included 16 samples without heart failure, 86 patients with dilated cardiomyopathy (CMP), and 108 patients with ischemic heart disease.11 The GSE3586 dataset included 13 patients with dilated cardiomyopathy and 15 patients without heart failure.12 The gene annotation files of GSE57345, GSE5406 and GSE3586 were GPL11532, GPL96, and GPL3050 respectively. GEO2R online tool was used for screening DEGs between HF and NFD with p < 0.05 (calculated by t-test) as the threshold.

The overlapping DEGs were uploaded to the Database for Annotation, Visualization, and Integrated Discovery (DAVID, https://david.ncifcrf.gov/) and Metascape (http://metascape.org/) databases for Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses respectively. P<0.05 was considered statistically significant.

The protein-protein interaction (PPI) network was constructed using the STRING database, and visualized with the Cytoscape software (3.7.2). DEGs with connectivity 5 in the PPI network were considered to be the hub genes.

The R package WGCNA was used to construct the weight co-expression network of the GSE57345 dataset. The GSE57345 dataset was used in the WGCNA analysis because it contained the largest sample size. The weighing coefficient was first calculated based on R2> 0.9 of the scale-free real biological network. After determining the adjacency function parameter , a hierarchical clustering tree of different gene modules was constructed. The Pearson correlation coefficient was then used to transform the correlation matrix into an adjacency matrix and subsequently to a topological overlap matrix (TOM).

The correlation among the genes in the aforementioned modules was analyzed and a heatmap was constructed. The module most closely related to the HF state was considered the key module of HF. To verify specific modulus-character associations, the correlation between GS and MM was investigated. Genes with |MM| > 0.8 were subsequently screened out as hub genes in the key module. The intersecting hub genes between the key module and the DEGs were finally defined as the hub genes of HF.

We used the GSE57345, GSE5406, and GSE3586 datasets to confirm the identity of the hub genes that may be associated with HF. Then, we used the t-test to determine the significance of the correlation between the expression of hub genes and HF. Receiver operating characteristic (ROC) curves were drawn for the core genes in the three datasets, and the area under the curve (AUC) was calculated. Specificity, sensitivity, and net reclassification index (NRI) were calculated to evaluate the value of the genetic diagnosis.

GSEA was performed to clarify the biological functions of the hub genes using the KEGG gene set (c2.cp. kegg. v7.2.) as the default and p < 0.05, as the threshold. The HF samples of the GSE57345 data set were divided into high and low expression groups of each hub gene. The enrichment graph was plotted using the clusterProfiler package of the R language and GSEA function.

The CMap database includes 1309 compounds and expression data of > 7000 human genes. The DEGs intersecting GSE57345, GSE5406, and GSE3585 datasets were uploaded to CMap. The negatively correlated small molecules were screened out using p < 0.0001 and mean < 0.4 as the criteria. ChemBioDrawUltta 17.0 software (http://www.chemdraw.com.cn) was used to draw the 3D structural formulas of potential therapeutic drugs and save them in mol2 format as small molecule compounds. The 3D crystal structures of the core targets were downloaded from the UniProt database (https://www.uniprot.org/). The Surflex-Dock module of SYBYL2.1 software was used for molecular docking, with total score >4 as the threshold for binding ability. The docking results were visualized using the Pymol software.

A total of 583 DEGs were identified between the HF and NFD samples across three GEO datasets (Figure 2AD). The most significantly enriched GO terms pertaining to biological process (BP) were negative regulation of angiogenesis (p = 1.55E-04), response to endoplasmic reticulum stress (p = 6.63E-04), heart development (p = 0.002463), regulation of ventricular cardiac muscle cell action potential (p = 0.004523), MAPK cascade (p = 0.005025), and blood vessel development (p =0.007107) (Figure 3A and Table S1). The cellular components (CC) terms including extracellular exosome (p =2.72E-08), cytoplasm (p =9.57E-06), actin cytoskeleton p (p =4.94E-05), mitochondrion (p =8.84E-05), nucleoplasm (p =1.03E-04), Golgi apparatus (p =1.21E-04) and lysosome (p =6.84E-04) were significantly enriched (Figure 3B and Table S1). The top enriched molecular function (MF) terms were activating transcription factor binding (p = 0.003852), actin filament binding (p =0.006599), cadherin binding involved in cell-cell adhesion (p = 0.00701), transcription coactivator activity (p =0.018332) and collagen binding (p =0.034108) (Figure 3C and Table S1). In addition, KEGG analysis revealed that the Ras signaling pathway (p =5.15548E-07), Focal adhesion (p =1.11814E-05), Lysosome (p = 2.43906E-05), MAPK signaling pathway (p = 4.23641E-05), PI3K-Akt signaling (p = 4.85396E-05), Protein processing in endoplasmic reticulum (p = 5.21303E-05) and Hippo signaling pathway (p =7.03525E-05) were significantly enriched among the DEGs (Figure 3D and Table S1).

Figure 2 The DEGs between HF and NFD. The volcano plots of DEGs in (A) GSE57345, (B) GSE5406 and (C) GSE3586. (D) Venn diagrams of DEGs in three data sets.

Figure 3 GO and KEGG pathway enrichment analysis. Significantly enriched GO terms for (A) Biological processes, (B) Cellular component, (C) Molecular function. (D) KEGG pathway Molecular function p < 0.05 is considered statistically significant.

A total of 1589 genes were screened from the GSE57345 dataset for WGCNA (p < 0.05, |Log2FoldChange| > 0.5). Sample clustering showed no significant differences in the WGCNA (Figure 4A). At = 4, the scale-free network fitting index R2 was 0.9, and the average connectivity approached 0, indicating that this value could obtain a scale-free network that met all requirements. Thus, = 4 was selected to construct a scale-free network (Figure 4BC). A dynamic shearing algorithm was used to cluster the genes and module divisions.

Figure 4 Determination of soft-threshold power . (A) Clustering dendrogram of 319 samples. (B) Scale-free topology fit index as a function of the soft-threshold power. The red line indicates that R2 is equal to 0.9. (C) Mean connectivity as a function of the soft-threshold power.

Five gene co-expression modules were finally obtained by calculating the module feature vector of each and merging similar modules (Figure 5A). The genes were clustered in the black, blue, yellow and green-yellow modules, and those that could not be clustered into any module were specified to the gray module. The yellow module with 73 genes showed the strongest correlation with HF (r = 0.77, p = 1e-61) (Figure 5B), as well as with the clinical phenotype as per GS and MM analyses (cor = 0.96, p = 5.5e-41; Figure 5CG). The genes distributed in the upper right corner were closely related to HF pathogenesis, and are likely the key disease genes. Twenty-one genes in the yellow module were confirmed as hub genes.

Figure 5 Identification of key HF gene modules. (A) Clustering dendrograms of genes and module detecting. (B) Heat map of the correlation between HF modules. (CG) Correlation of GS and MM in the HF-related module. p < 0.05 is considered statistically significant.

From the 583 overlapping DEGs, 322 hub genes were selected for subsequent analysis (Figure 6A). The key intersecting genes between the 322 hub DEGs and 21 hub genes of the yellow module included PTN, LUM, ISLR and ASPN. The expression levels of these potentially key genes were analyzed in the HF and NFD samples of the GSE57345, GSE5406 and GSE3586 datasets. We further visualized their expression levels in the GSE57345 data set, and found that all four genes were overexpressed in HF samples compared to the NFD group (p < 0.05, Figure 6B). Afterwards, the genes were verified in GSE5406 and GSE3586, which verified higher expression levels in the HF group (p < 0.05, Figure 6C and D).

Figure 6 Analysis of key genes. (A) The Venn diagram of hub genes in the yellow module and hub genes in DEGs. Expression of PTN, LUM, ISLR and ASPN in the (B) GSE57345, (C) GSE5406 and (D) GSE3586 datasets. **p < 0.01 and ***p < 0.001 are considered statistically significant.

The potential diagnostic value of PTN, LUM, ISLR and ASPN was ascertained by plotting the ROC curve based on the expression data in GSE57345, GSE5406 and GSE3586. As shown in Figure 7AC, the AUC of all genes in all datasets exceeded 0.9, except for 0.785 calculated for ISLR in GSE3586. We uploaded AUC and Standard Error data into MedCalc software, and applied the Z test to compare the expression of PTN, LUM, ISLR and APSN between the datasets. The results showed that there was no statistical difference (p >0.05). We used the NRI to analyze differences in the expression levels of the four predicted HF hub genes in the GSE57345, GSE5406 and GSE3586 datasets. The PTN and ISLR of the GSE5406 dataset showed significant differences in predicting HF (NRI [95% CI]: 0.3228 [0.03610.6095], p: 0.027); the prediction effects of the PTN and ISLR genes were significantly different, NRI [95% CI]: 0.3905 [0.00730.7736], p: 0.045). The prediction effects of ISLR and LUM gene in the GSE5406 dataset were significantly different (NRI [95% CI]: 0.5077 [0.93610.0793], p: 0.020). Subsequently, ROC analysis was performed to determine the diagnostic value of the four key genes, and the results suggested that these four hub genes can diagnose HF with high sensitivity and specificity (Table 1).

Table 1 ROC Curve Analysis of Hub Genes

Figure 7 The ROC curve of hub genes (A) GSE57345. (B) GSE5406. (C) GSE3586. The x-axis shows specificity, and the y-axis shows sensitivity.

Abbreviations: ROC, receiver operating characteristic; AUC: area under the ROC curve.

GSEA of PTN, LUM, ISLR and ASPN revealed direct involvement in the pathogenesis of HF. As shown in Figure 8AD, all genes were enriched in arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy, ecm receptor interaction, focal adhesion, gap junction, hypertrophic cardiomyopathy (HCM), regulation of actin cytoskeleton and TGF- signaling pathway. In addition, PTN, LUM and ASPN were enriched in the WNT signal pathway, LUM in the calcium signaling pathway, and ASPN is likely involved in seleno-amino acid metabolism.

Figure 8 Results of GSEA. (A) PTN. (B) LUM. (C) ISLR. (D) ASPN.

There were 264 upregulated and 499 down-regulated genes intersecting across the three datasets. The genes were uploaded to the cMap database to filter out negatively related small molecule compounds (p < 0.0001 and mean < 0.4). Sirolimus, LY-294002, and wortmannin were identified as potential drugs of HF (Figure 9AC). Molecular docking showed that sirolimus had good affinity for PTN, ISLR, LUM, and ASPN, and wortmannin for PTN and LUM (Figure 9D). The molecular docking diagrams of potential compounds and hub targets are shown in Figure 9EJ.

Figure 9 The potential therapeutic drugs of HF. (AC) The 2D structure of Sirolimus, LY-294002 and Wortmannin. (D) Heat map of the docking score between potential drugs and hub targets. The intensity of red color indicates binding ability. (EJ) Molecular docking diagram of certain core compounds and hub targets.

In this study, we combined WGCNA and DEGs to screen for genes associated with HF and found that the expression levels of the PTN, ISLR, LUM, and ASPN genes were all upregulated in HF. Further analysis using the ROC curve showed that these four genes may be potential biomarkers of HF. At present, PTN and ISLR have not been reported to be associated with HF, but there is evidence that they may be potentially associated with HF. Single-gene GSEA showed that the hub genes of HF are related to arrhythmic right ventricular cardiomyopathy, dilated cardiomyopathy and hypertrophic cardiomyopathy, which is consistent with reports demonstrating that these cardiovascular disorders precede the final HF stage.1315 Single-gene GSEA showed that the hub genes of HF are related to arrhythmic right.

GO analysis of the DEGs showed that endoplasmic reticulum stress (ERS) is closely related to HF pathogenesis, which is consistent with previous reports.1618 The risk factors of HF can induce ERS in myocardial cells, which culminates in apoptosis and cardiovascular dysfunction. In addition, the DEGs were enriched in ferroptosis, MAPK signaling pathway, PI3K-Akt signaling pathway, and the Hippo signaling pathway, all of which are involved in HF. Liu et al19 detected a high level of ferroptosis in the cardiomyocytes of a rat model of pressure overload-induced HF. Exogenous expression of ferritin FTH1 and GPX4 and reduction in ROS levels through NOX4 knockdown inhibited ferroptosis in cardiomyocytes and improved cardiac function. Fang and Koleini et al20,21 found that doxorubicin induced the accumulation of oxidized phospholipids in undifferentiated cardiomyocytes and up-regulated heme oxygenase1 (HMOX1), resulting in heme degradation, free iron overload, and ferroptosis, which eventually leads to HF. The loss of myeloid differentiation protein 1 (MD1) activates ROS and exacerbates autophagy induced by the MAPK signaling pathway. Therefore, the MD1-ROS-MAPK axis is a novel therapeutic target for HF that can preserve the ejection fraction.22 Mao Liu et al23 showed that paeoniflorin reduced myocardial fibrosis and improved cardiac function in rats with chronic HF by regulating the p38/MAPK signaling pathway. Apelin-13 can slow down oxidative stress by inhibiting the PI3K/Akt signaling pathway in the rat HF model and ameliorate angiotensin IIinduced cardiac insufficiency, impaired cardiac hemodynamics, and fibroblast fibrosis.24 Hou and Li et al25,26 showed that YAP/TAZ can initiate the transcription of connective tissue growth factor by interacting with the TEAD domain family, increase the expression of extracellular matrix genes, promote cardiac remodeling and fibrosis, and thus delay the progression of HF. Leach et al27 found that knocking out the SALV gene increased the number of left ventricular myocardial cells in mice with myocardial infarction, which reduced ventricular fibrosis and increased the number of new capillaries around the injured myocardium, indicating that the Hippo signaling pathway can enhance heart function.

PTN is a highly conserved proto-oncogene closely related to tumor angiogenesis and metastasis.28 It is highly expressed in various malignant tumors, such as breast cancer, prostate cancer and rectal cancer,29,30 and promotes the proliferation, mitosis, differentiation, and migration of vascular endothelial cells.31 Overexpression of PTN gene can promote bone formation, whereas PTN gene knockout mice have dysfunctional bone growth and remodeling.32 LUM is a member of the SLRP family of leucine-rich proteins that are secreted by the extracellular matrix. It is widely distributed in various tissues, and shows aberrant expression levels in pancreatic cancer, colorectal cancer, breast cancer and cervical cancer.33 LUM has both oncogenic and tumor-suppressive functions depending on the cancer type. For instance, LUM facilitated the metastasis of colon cancer cells by reconstructing the actin cytoskeleton, but inhibited the adhesion of osteosarcoma cells via the TGF-2 signaling pathway.34,35 ISLR is a conserved immune-related protein that is mainly expressed in stromal cells.36 Xu et al37 showed that ISLR can inhibit Hippo signal transduction during intestinal regeneration and tumorigenesis and activate YAP factor in epithelial cells. Knocking out ISLR in mouse stromal cells significantly affected intestinal regeneration and inhibited colorectal tumorigenesis. Zhang and Hara et al38,39 further showed that the ISLR can promote muscle regeneration and improve myocardial tissue repair. However, little is known regarding the correlation between ISLR and HF. ASPN is an extracellular matrix protein and a member of the leucine-rich small proteoglycan family.40 Sasaki et al41 showed that ASPN protected gastric tumor cells against oxidative stress by up-regulating HIF1 and reducing the levels of mitochondrial ROS. It also increased the expression of CD44 to accelerate the migration and infiltration of gastric cancer cells. However, other reports indicate an anti-tumorigenic role of ASPN in breast cancer.42,43 Studies also show that ASPN is up-regulated during aortic stenosis or coronary artery ligation in ischemic cardiomyopathy patients and animal models.44 ASPN may also increase the apoptosis and fibrosis of H9C2 cardiomyocytes.45 However, the exact role of ASPN in HF pathogenesis needs further investigation.

Lu A et al46 found that Wnt3a binds to FZD and LRP5/6 receptors, thereby activating the classic Wnt-Dvl--catenin signaling pathway and promoting myocardial hypertrophy. Wnt signaling can inhibit Na+ channels by directly or indirectly inhibiting the expression of Scn5a. Thus, blocking these intracellular cascades is a rational therapeutic strategy against HF.46 He et al47 found that Wnt3a and Wnt5a ligand were up-regulated in a mouse model of cardiac hypertrophy, underscoring the role of the Wnt signaling pathway in HF pathogenesis. TGF- is an important factor regulating myocardial fibrosis, which gradually worsens during HF and alters cardiac function from the compensatory phase to the decompensated phase.48 Kakhi et al49 found that sirolimus, an mTOR inhibitor, reversed new HF after kidney transplantation in mammals. Gao et al50 also showed that rapamycin (sirolimus) can reduce cardiomyocyte apoptosis and promote autophagy by regulating mTOR and ERS, thus preventing myocardial damage caused by chronic HF. LY294002 and wortmannin are protein kinase inhibitors that block the PI3K signaling pathway. Melatonin alleviates cardiac hypertrophy by inhibiting the Akt/mTOR pathway and reducing Atg5-dependent autophagy, which can be reversed by LY294002.51 Studies show that apelin may reduce the myocardial damage caused by acute HF by regulating the APJ/Akt/ERS signaling pathway. However, wortmannin and LY294002 can reverse the cardioprotective effects of apelin.52 The PI3K-Akt signaling pathway was also enriched among the HF-related DEGs, indicating a vital mechanistic role in its pathological progression. Molecular docking showed that sirolimus and wortmannin had a high affinity to the hub targets, LY-294002 bound weakly and may therefore have other targets. Nevertheless, all three drugs could be potentially effective for treating HF.

There are several limitations in this study. First, the data used in this study was obtained from the GEO database, which lacks clinical, in vivo, and in vitro experimental research certifications for pivotal genes and HF-associated genes. Second, the datasets used in this study were relatively small, and a larger sample size is needed to verify our results. However, our findings provide new insights into the underlying molecular mechanisms of HF, along with potential diagnostic biomarkers and candidate therapeutic drugs, which will help provide new clues for HF research, diagnosis and treatment, and target selection.

PTN, LUM, ISLR, and ASPN are overexpressed in HF patients compared to NFD, and are mainly related to the TGF- and Wnt signaling pathways. Sirolimus, LY-294002, and wortmannin are potential drug candidates for HF treatment. The in silico data will need to be verified by functional and clinical studies.

All datasets generated and analyzed during the current study were uploaded with the manuscript as additional files.

The ethics committee of the Qinghai University has waived the need for ethical approval for the reasons that the present study used public database, so it did not involve ethics.

This research was supported by the Technology Department project of Qinghai Science (No. 2020-ZJ-922).

The authors report no conflicts of interest in this work.

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Mary Katherine Melroy, 40, was relieved when a mammogram in November 2020 determined that the lump she found in her breast wasnt a cause for concern. What was concerning, however, was her risk assessment score for developing breast cancer.

She was referred to the High-Risk Breast Evaluation Clinicat MUSC Hollings Cancer Center, where she met with a genetic counselor and completed testing to search for clues that may have put her at a greater risk of developing an inherited form of breast cancer. Thats when she learned she had a pathogenic mutation in the CHEK2 gene and a 25% to 39% chance of developing breast cancer in her lifetime more than double the risk of the average U.S. woman. The mutation also increases her risk of developing colon and thyroid cancer.

Instead of panicking, Melroy was comforted by the news. It gave her the answers shed been searching for when her mom was diagnosed with breast cancer 10 years ago at the age of 58.

It was actually a relief because it made sense, said Melroy, who never understood how breast cancer could affect someone as petite, healthy and fit as her mom. It didnt give me anxiety to know I had this mutation. It put the ball in my court to do what I need to do.

Melroy got to work researching her mutation and learned that opting to have a bilateral mastectomy a surgery used to remove both breasts could reduce her risk of breast cancer to 5%. After watching her mom struggle with the side effects of chemotherapy, she decided she wanted to do everything in her power to reduce her risk of going through the same thing. She plans to get the surgery toward the end of 2021.

Knowing shes at increased risk of cancer is empowering for Melroy, as she feels like she has options for shaping her future.

As an adult, there are very few things that I feel like I can control, but this is a piece of the puzzle of my health that I can take control of. Id rather get the surgery than go in for screenings twice a year because Id feel like we were just waiting until we found something, said Melroy, who also plans to talk with her doctor about getting screened early for colon cancer.

Theres so much you can do when you have the knowledge. A lot of people are scared at the thought of getting genetic testing, but whats scary to me is looking at what happened to my mom.

At Hollings, the demand for genetic testing has risen 422% in the last year. In response, the genetic counseling program is the largest it has ever been, employing six counselors total, two of whom provide full-time onsite services for Hollings patients.

While genetic testings popularity took off in 2013 following a Supreme Court case that allowed more than one company to test for certain genetic mutations, it continues to become more common as testing guidelines expand to include more people. Its now recommended that all pancreatic, ovarian and high-risk prostate cancer patients be referred for testing, and talks of including all breast cancer patients are in the works.

According to Libby Malphrus, one of Hollings onsite counselors, the ability of Hollings program to grow with the demand is one thing that makes it unique.

Theres a shortage of genetic counselors nationally. The access people have to genetic counselors at Hollings is huge and something most large health care systems strive for, said Malphrus. We have a multitude of counselors and various ways in which we can deliver that service, including through telemedicine, and thats a huge asset.

Because the program is still growing, genetic counseling currently is only available to current cancer patients or those deemed at high risk of developing cancer based on their family history. For patients who already have cancer, genetic testing can help to inform their treatment plans, from determining which surgical techniques should be used to how aggressively the cancer should be treated.

It can also determine whether theyre at risk of developing other cancer types and whether their family members may need increased surveillance.

While the information found can potentially be lifesaving for cancer patients and their families, Charly Harris, the programs other full-time genetic counselor, reminds patients that testing also comes with risks.

When someone is diagnosed with cancer, they dont want to think about whether there are other cancer types for which they may be at risk. Their diagnosis is often already a big surprise for them, so adding additional cancer risks can be too much information in that moment, said Harris, who noted Hollings counselors meet with patients prior to testing to discuss the pros and cons.

Malphrus added, Its hard enough for individuals to battle their diagnoses and watch the emotional impact that has on their families without the thought that they could be passing that gene on to their children. Thats heavy information, which is why we dont want anyone to assume they should be tested just because they have cancer.

Melroy understands the information found through her testing affects not only her own health but the health of her sisters, brother and children. Shes already planning on having her 6-year-old daughter tested when shes old enough.

While the technology used in genetic testing continues to grow in speed and efficiency, Malphrus and Harris acknowledge theres still a lot that is unknown about how to use the results. Finding a mutation by testing more genes isnt helpful if counselors dont know what that mutation means.

Thats why its important for patients to have testing done through a genetic counselor who is trained in medical genetic testing as opposed to companies offering direct-to-consumer DNA testing. Direct-to-consumer tests only examine a small number of genes, giving an incomplete picture of potential health risks. The test at Hollings examines up to 84 genes that are known to be associated with an increased cancer risk.

While certain cancers, like breast and ovarian, are more strongly associated with hereditary factors than others, most cancers are not inherited. In fact, only 5% to 10% of breast cancers and 20% to 25% of ovarian cancers are hereditary, which is why getting regular cancer screenings is important regardless of genetic testing results.

People often think, I dont have a family history, so its not going to happen to me, said Harris. I always remind my patients that they still have the general population risk of all cancers. Just because weve lowered the risk for hereditary cancers doesnt mean they dont need to continue getting screened.

Individuals can lower their cancer risks through lifestyle choices such as maintaining a healthy weight and diet, getting regular exercise, avoiding smoking and staying on top of their preventive care. Additionally, getting the HPV vaccine can protect against six types of cancers.

While Harris and Malphrus both entered genetic counseling due to their love of the science, they agree that the most rewarding part of their job is giving patients a sense of control over something they often feel they cant change.

Genetics is complicated, and its only becoming more complex, said Malphrus. Its rewarding to be that bridge between science and medicine and to help people to make educated choices that are best for themselves and their families.

Originally posted here:
Genetic counseling program helps patients take control of their health - Medical University of South Carolina

A one-year-old Emirati baby Afra with a progressive muscular disease has been successfully treated with an advanced genetic treatment that will prevent further deterioration. Image Credit:

Abu Dhabi: A one-year-old Emirati baby with a progressive muscular disease has been successfully treated with an advanced genetic treatment that will prevent further deterioration.

Baby Afra was diagnosed with spinal muscular atrophy (SMA), an inherited disease that damages nerve cells, called motor neurons, in the spinal cord. The most common form of the rare neuromuscular disease involves an abnormal or missing survival motor neuron 1 gene (SMN1 gene).

I first noticed abnormal movements in Afra when she was only three months old and quickly consulted a paediatric physician. After multiple tests, Afra was diagnosed with SMA, and transferred to the Sheikh Khalifa Medical City (SKMC), said Afras mother said.

Genetic medicine

The SKMC medical team sprang into action and developed a comprehensive treatment plan to prevent further deterioration. This included importing a genetic medicine, which has viral vectors that target the affected neurons, inserting copies of normal SMN1 genes inside. Following this, the muscle condition improves in terms of movement and function.

Afras journey towards recovery is a significant achievement, not just for the A u Dhabi Health Services Company (Seha) network [which includes SKMC], but for the wider healthcare ecosystem in the country, as we provide hope and create impact for families with children diagnosed with SMA, said Dr Mariam Al Mazrouei, SKMC chief executive director.

Early intervention

The key to successfully overcoming SMA is early diagnosis and implementation of a vigorous treatment strategy. This keeps the neurons as intact as possible and prevents further damage, said Dr Omar Ismail, paediatric neurology consultant and head of paediatric neurology at the hospital.

In Afras case, even though she was brought in quite late with affected limbs, we quickly jumped into action with an inclusive treatment plan that prevented further deterioration of her muscles while we waited for the required genetic treatment to arrive from abroad. This particularly helped with Afras breathing muscles, and eliminated the need for an artificial respiratory device, Dr Ismail said.

Baby Afra will continue to be followed up by doctors at SKMC.

The medical team has implemented a robust treatment plan. I am tremendously grateful to them for their diligence in treating my daughter, Afras mother said.

Prevalence

According to the Centre for Arab Genomic Studies, the prevalence of SMA in GCC populations is thought to be at least 50 times higher than in the United States, with more than 50 cases per 100,000 live births, compared to only 1.2 in the United States. It is one of the diseases that the Abu Dhabi Emirates Premarital Screening and Counselling Programme screens for, before couples wed, in order to alert couples about possible risk.

Read more here:
One-year-old baby in UAE receives imported genetic medicine to treat rare disease - Gulf News

The findings challenge past, smaller studies that found Black women face a greater genetic risk [for breast cancer] and the suggestion that race should be an independent factor when considering genetic testing, said first authorSusan Domchek, MD,executive director of the Basser Center for BRCA.2

Investigators studied 3946 Black and 25278 non-Hispanic White women, with 5.6% and 5.06%, respectively, found to have 1 of 12 genes linked to breast cancer. The study looked at the main PVs in genes, tumor estrogen receptor (ER) status, and age.

PVs in 3 different genesCHEK2, BRCA2, and PALB2were found to be the most statistically different between the two races. For CHEK2, non-Hispanic White women were more likely to have PVs than Black women (1.29% vs 0.38%; P < .001). For BRCA2, Black women were more likely to have PVs than non-Hispanic White women (1.80% vs 1.24%; P = .005); in PALB2, more PVs were noted in Black women (1.01% vs 0.40%; P < .001).

In ER-positive breast cancer, Black women were more likely to have BRCA2 (1.56% vs 1.05%; P = .04) and were less likely to have CHEK2 (0.46% vs 1.36%; P < .001) PVs compared with white women. There was a higher prevalence of PALB2 PVs in Black vs non-Hispanic women with ER-negative breast cancer (1.83% vs 0.95%; P = .04) and triple-negative breast cancer (2.79% vs 1.23%; P = .05). BRCA1, BRCA2, and PALB2 accounted for 75% of PVs in ER-negative cases, at rates of 81.3% in Black women and 77.0% in non-Hispanic White women.

The investigators found that there was no difference in rates of PVs by age of diagnosis before 50 years (8.83% of Black vs 10.04% of non-Hispanic White women; P = .25). CHEK2 was more likely to occur in non-Hispanic White women than Black women diagnosed under the age of 50 (1.82 vs 0.43; P <.001). Adjusting for age, it was found the prevalence ration was 1.08 for the comparison of non-Hispanic and Black women (1.08; 95% CI, 1.02-1.14). In PALB2, there was a higher standardized prevalence ratio for PVs in Black women (.40; 95% CI, 0.33-0.38) whereas CHEK2 had a lower prevalence (3.35; 95% CI, 3.01-3.74) by age.

After age adjustment, there was no longer a prevalence difference found for BRCA2, with a standardized ratio of 0.91 (95% CI, 0.81-1.01). Notably, 4 PVs of ATM, BRCA1, RAD51D, and TP53 showed significant association with ethnicity when age was adjusted, whereas no such correlation was seen previously.

Investigators noted that one limitation of this study was unknown family history of patients. They also had a very small group of patients with RAD51C and RAD51D to be able to draw conclusions about prevalence.

At a time when Black men and women are more likely to be diagnosed with cancer at later stages when it is less treatable, [the Black & BRCA initiative] seeks to empower people to understand their family health history and take action to prevent cancer from one generation to the next, Domchek said.

References

1. Domchek SM, Yao S, Chen F, et al. Comparison of the prevalence of pathogenic variants in cancer susceptibility genes in black women and non-hispanic white women with breast cancer in the United States. Published online May 27, 2021.JAMA Oncol. doi:10.1001/jamaoncol.2021.1492

2. Black and white women have same mutations linked to breast cancer. News Release. Penn Medicine. June 11, 2021. Accessed June 16, 2021. https://bit.ly/3qfH6qP

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Black and non-Hispanic White Women Found to Have No Differences in Genetic Risk for Breast Cancer - Cancer Network

By Dr. DeLon Canterbury

Ever wonder why you may take a medication and have side effects, but a family member takes the same medication and does fine? Although your age, sex, weight, and health conditions could be factors

The answer may be in your genes!

Regardless of race, ethnicity, or gender, nearly 99.9 percent of EVERYONEs DNA is similar. For that 0.1 percent, there can be significant gene changes that impact how well or how poorly you tolerate a specific medication.

In other words, your DNA can affect whether you have a bad reaction to a drug, if a drug helps you, or has no effect.

Pharmacogenomics (Gene Testing/Precision Medicine) looks at how your DNA affects the way you respond to drugs. Its the study of specific gene changes that influence whether a medication could be lifesaving for one but potentially fatal for another.

The use and study of drug-gene testing has been around for 20 years. In the beginning, most insurance carriers did not cover it. Now, pharmacogenomics is widely available and affordable.

So why are you just hearing about Pharmacogenomics?

Sadly enough, health care still is not accessible to everyone, even those who have the best access still may not get the best answers!

As a concerned pharmacist with a passion for health equity and medication, GeriatRx can provide gene testing, identify potentially rare genetic disorders, as well as prevent you from taking ineffective and expensive medications.

It baffles me that the antibiotics, blood pressure, anxiety, and several other drugs we use daily were best assessed for a group of people that does not truly reflect the melting pot we proudly call USA.

Most modern, medicinal and pharmacological practices seen in our American health system stem from outdated, clinical studies with an overwhelming majority of white male subjects. Yes, we bleed the same, but how we respond to the drugs we take regularly, can be completely different!

GeriatRx has an absolute responsibility in sharing how using genetic tests can stop harmful and fatal medications from entering your body! GeriatRx works with your provider on how to best prescribe new drugs.

Want to know whats in your genes?

Get a personalized genetic test from an accessible and trusted pharmacist who can provide genetic testing anywhere in the country, GeriatRx.

Let GeriatRx advocate for you.

Dr. Canterbury, president/CEO of GeriatRx, Inc., is a Board-Certified Geriatric Pharmacist who focuses on the special needs of older patients that may have concurrent illnesses taking multiple medications. He is being trained as a Medicare and Medicaid specialist through the Seniors Health Insurance Information Program (SHIIP) and is a member of Durham, North Carolinas, African American COVID Task Force.

To learn more about GeriatRx and pharmacogenomics, contact Dr. Canterbury@cell: 404-484-5092; website: http://www.geriatrx.org; email: geriatrxinc@gmail.com.

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What's in your genes | The Crusader Newspaper Group - The Chicago Cusader