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TUESDAY, March 29, 2022 (HealthDay News) -- Babies born to fathers who were taking the common diabetes drug metformin may have a slightly increased risk of certain birth defects, a large new study suggests.

Among over 1 million babies born in Denmark, just over 3% had a birth defect of some kind. But that rate was roughly 5% among babies whose fathers had used metformin in the three months before they were conceived, the findings showed.

In particular, the medication was tied to a higher risk of genital birth defects, all in baby boys, according to the report published March 28 in the Annals of Internal Medicine.

Experts stressed that the study does not prove metformin is to blame, and there is no known mechanism to explain the connection. And men should not stop using their medication based on a single study, they added.

"We know metformin works well for controlling diabetes," said senior researcher Dr. Michael Eisenberg, a professor of urology at Stanford University School of Medicine in California.

But the results do bring up a "signal" that should be studied further, Eisenberg said. On a broader level, he added, the study highlights the importance of understanding fathers' influence on birth defect risks.

Metformin is an oral medication widely used for controlling high blood sugar in people with type 2 diabetes a common disease that is often related to obesity.

In the United States alone, more than 37 million people have diabetes, most of whom have type 2, according to the U.S. Centers for Disease Control and Prevention. While it is most common in people older than 45, the agency says, type 2 diabetes is increasingly being diagnosed in younger adults and even children and teenagers.

Studies have found that when pregnant women have poorly controlled diabetes, their babies' risk of birth defects rises.

Meanwhile, some research has tied diabetes in men to poorer sperm quality. But it has not been clear whether fathers' diabetes is related to the odds of birth defects in their children.

Even then, Eisenberg said, a key question would be whether it is because of the diabetes or the medications used to treat it?

For the new study, the researchers turned to Denmark's national birth registry, analyzing data on over 1 million babies born between 1997 and 2016.

The investigators found that when fathers had used metformin within the three months before conception, their babies' risk of birth defects was about 40% higher, on average, versus the study group as a whole.

There was a particular link to genital birth defects, all among boys: Of all babies whose fathers used metformin in the three months before conception, 0.9% had a genital birth defect, versus just over 0.2% of the overall group.

That three-month window is critical, Eisenberg said, because sperm take roughly that long to develop.

The researchers dug into other factors that might explain the link, including parents' age, education level and smoking habits. But fathers' metformin use remained tied to birth defect risk.

That still left the question of whether it was the medication, or the diabetes.

There were some strikes against that notion, Eisenberg said. For one, there was no clear link between birth defects and fathers' metformin use in the year before or after the three-month window before conception.

The researchers also looked at two other types of diabetes medication used by fathers in the study: insulin and drugs called sulfonylureas. Insulin use was not tied to birth defects.

On the other hand, there was an elevated rate of birth defects when fathers used sulfonylureas. But the finding was not "statistically significant" once the researchers weighed other factors meaning it could have been due to chance.

However, an expert not involved in the study said the metformin finding could also easily be due to chance, or "confounding" due to other factors.

Dr. Anthony Scialli is a member of the Organization of Teratology Information Specialists. The group runs MotherToBaby, a free service that provides research-based information on the effects of medications during pregnancy.

Scialli explained that the study made many different comparisons, which increases the odds of chance findings. Beyond that, he said, genetic factors could be at play.

Scialli noted that the genital birth defects in boys would mostly be hypospadias, where the opening of the urethra is on the underside of the penis rather than the tip. And hypospadias, he said, often runs in families.

The researchers did do a comparison to try to account for genetics: They found that babies "exposed" to fathers' metformin use had a higher rate of birth defects than their siblings who were not exposed.

But, Scialli pointed out, that difference was not statistically significant once the researchers adjusted for other variables.

"So both chance and confounding could explain these results," Scialli said. "Causation seems unlikely given the lack of a plausible mechanism."

Eisenberg agreed that the mechanism is unknown, and more research is needed. He also said the findings need to be replicated in other countries, including ones more diverse than the relatively homogenous Denmark.

The bigger point is that fathers' health and exposures, and their potential impact on their children, should not be ignored, Eisenberg said.

"The health of fathers matters, too," he said.

More information

MotherToBaby has more on fathers' exposures and pregnancy.

SOURCES: Michael Eisenberg, MD, professor, urology, Stanford University School of Medicine, Stanford, Calif.; Anthony Scialli, MD, reproductive and developmental toxicology specialist, member, Organization of Teratology Information Specialists, Brentwood, Tenn.; Annals of Internal Medicine, March 28, 2022, online

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Rise in Birth Defects for Babies Whose Fathers Took Common Diabetes Drug - HealthDay News

LONDON--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that as of 1 April 2022, TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor) will be reimbursed on the Australian Pharmaceutical Benefits Scheme (PBS) for the treatment of cystic fibrosis (CF) in people ages 12 years and older who have at least one F508del mutation in the CFTR gene, the most common CF-causing mutation worldwide.

Todays announcement is a significant milestone in ensuring Australians living with CF receive timely and sustainable access to TRIKAFTA, said Ludovic Fenaux, Senior Vice President, Vertex International. This is the fourth treatment we have brought to Australians over the last eight years, working tirelessly alongside the CF patient and clinical communities. We thank the Australian Government for recognizing the significant need for TRIKAFTA and the value it brings.

TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor) was approved by the Australian Therapeutic Goods Administration (TGA) in March 2021 based on the results of four global Phase 3 clinical trials, which included multiple Australian trial sites and patients.

CF is a rare, life-shortening, genetic disease affecting approximately 3,500 people in Australia. It is caused by a defective and/or missing CFTR protein, resulting from mutations in the CFTR gene. Up to 90 percent of people living with CF have at least one F508del mutation.

As a genetic disease, cystic fibrosis is a prime candidate for precision medicine. Now, with PBS listing of TRIKAFTA, eligible Australians living with CF ages 12 years and older can broadly access a therapy that treats the underlying cause of their disease. Clinicians across Australia will be excited about this most welcome news, said Professor John Wilson AM, Head, Cystic Fibrosis Service, Alfred Health Australia.

Australia now joins the list of 30 countries where the triple combination therapy is approved and reimbursed including Denmark, Finland, France, Germany, Italy, Ireland, Israel, Poland, Spain, Switzerland and the countries within the U.K.

About Cystic Fibrosis

Cystic fibrosis (CF) is a rare, life-shortening genetic disease affecting more than 83,000 people globally. CF is a progressive, multi-organ disease that affects the lungs, liver, pancreas, GI tract, sinuses, sweat glands and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. Children must inherit two defective CFTR genes one from each parent to have CF, and these mutations can be identified by a genetic test. While there are many different types of CFTR mutations that can cause the disease, the vast majority of people with CF have at least one F508del mutation. CFTR mutations lead to CF by causing the CFTR protein to be defective or by leading to a shortage or absence of CFTR protein at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus, chronic lung infections and progressive lung damage that eventually leads to death for many patients. The median age of death is in the early 30s.

About TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor)

In people with certain types of mutations in the CFTR gene, the CFTR protein is not processed or folded normally within the cell, and this can prevent the CFTR protein from reaching the cell surface and functioning properly. TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor) is an oral medicine designed to increase the quantity and function of the CFTR protein at the cell surface. Elexacaftor and tezacaftor work together to increase the amount of mature protein at the cell surface by binding to different sites on the CFTR protein. Ivacaftor, which is known as a CFTR potentiator, is designed to facilitate the ability of CFTR proteins to transport salt and water across the cell membrane. The combined actions of elexacaftor, tezacaftor and ivacaftor help hydrate and clear mucus from the airways.

For complete product information, please see the Summary of Product Characteristics that can be found on https://www.tga.gov.au/apm-summary/trikafta.

About Vertex

Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has multiple approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational small molecule, cell and genetic therapies in other serious diseases where it has deep insight into causal human biology, including sickle cell disease, beta thalassemia, APOL1-mediated kidney disease, pain, type 1 diabetes, alpha-1 antitrypsin deficiency and Duchenne muscular dystrophy.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 12 consecutive years on Science magazine's Top Employers list and one of the 2021 Seramount (formerly Working Mother Media) 100 Best Companies. For company updates and to learn more about Vertex's history of innovation, visit https://global.vrtx.com/ or follow us on Twitter and LinkedIn.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Ludovic Fenaux, Senior Vice President, Vertex International, and Professor John Wilson AM, Head, Cystic Fibrosis Service, Alfred Health, in this press release and statements regarding the reimbursement of and access to TRIKAFTA for certain patients, the estimated number of patients eligible for a CFTR modulator therapy in Australia, including patients that will now have access to a CFTR modulator therapy for the first time, and our beliefs about the benefits of our medicines. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the companys development programs may not support registration or further development of its compounds due to safety, efficacy, or other reasons, risks related to obtaining approval for and commercializing our medicines, and other risks listed under the heading Risk Factors in Vertex's annual report filed with the Securities and Exchange Commission (SEC) and available through the company's website at https://global.vrtx.com/ and on the SECs website at http://www.sec.gov. You should not place undue reliance on these statements. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

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Vertex Announces Reimbursement Agreement in Australia for TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor) for Patients With Cystic Fibrosis...

image:SRF is a 501(c)(3) public charity incorporated in 2018. The mission is to improve the quality of life of SYNGAP1 patients through the research and development of treatments, therapies and support systems. Completely parent led, SRF is the largest non-government funder of SynGAP research. The founders cover all operational costs, allowing 100% of donations to go to research. SRFs mantra is Collaboration, Transparency & Urgency. SRF is a member of combinedBrain, the Precision Medicine Coalition, the Global Genes RARE Foundation Alliance & the Everylife Foundation Community Congress. Learn more at SyngapResearchFund.org. view more

Credit: Syngap Research Fund

Syngap Research Fund & Rare Diseases Models and Mechanisms Network partner to co-fund two SYNGAP1 animal model studies in the labs of Dr. Graziella Di Cristo & Dr. Kurt Haas in Canada.

Christine Oriel of RDMM says, The Rare Diseases: Models and Mechanisms Network (RDMM) is happy to partner with SRF in co-funding these research projects. We look forward to seeing the research of Drs. Haas and Di Cristo to better understand the disease and identify and develop new therapies to treat SYNGAP1. SRF has done a lot to support SYNGAP1 research and we look forward to continuing with this partnership in the future.

Michael Graglia of SRF says, SRF is grateful to RDMM for co-funding these critical projects on SYNGAP1. We desperately need to better understand SYNGAP1 and develop therapies for our patients. This partnership allows us to both identify high-impact projects and then leverage funds raised from the families of affected patients. I am especially grateful to the Yassba family who generously supported this grant in honor of their son.

Dr. Graziella Di Cristo, Professor, Department of Neuroscience, Universit de Montral and the CHU Sainte-Justine Research Center says, "Sensory processing disorders, or the difficulty in receiving and responding to information that comes through the senses (hearing, vision, touch, etc.) are common in children with neurodevelopmental disorders. We have recently found alterations on how the brain responds to complex visual and auditory stimulations in children and in mouse models carrying mutations in the gene SYNGAP1. With this study, we hope to understand how specific neuron types contribute to these phenotypes in the mouse models. We hope that better understanding of the cellular underpinning of sensory processing disorders might help developing treatment strategies tailored and optimized towards these symptoms in SYNGAP1 patients.

Dr. Kurt Haas, Professor, Dept of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia says, Our lab recently reported results from our study of 57 missense mutations of SYNGAP1, many identified in individuals with Autism Spectrum Disorder (ASD). In contrast to the conventional model that SYNGAP1 mutations in ASD induce complete loss of protein function leading to haploinsufficiency, my team found that missense mutations induced selective deficits in pathways associated with either long-term potentiation (LTP) or depression (LTD) forms of synaptic plasticity. Here, we will follow up this study by directly testing how these SYNGAP1 mutations impact synaptic plasticity in neurons within intact neural circuits.

SYNGAP1-related intellectual disability (US ICD-10: F78.A1) is a rare genetic disorder caused by a variation on the SYNGAP1 gene, with nearly 1,000 diagnosed patients accounted for globally as of December 2021. It leads to several neurological issues in patients, including intellectual disability, epilepsy, autism, sleep challenges, gastro-intestinal and feeding problems, hypotonia (low muscle tone), apraxia (delayed/no speech), impulsivity and aggression. (Vlasskamp, 2019)

ABOUT SYNGAP RESEARCH FUND

SRF, incorporated in 2018, is a 501(c)(3) US public charity whose mission is to improve the quality of life of SYNGAP1 patients through the research and development of treatments, therapies and support systems. Completely parent-led, SRF is the largest non-government funder of SynGAP research having committed over $2M in grants. The founders cover all operational costs, allowing 100% of donations to go to research. SRFs grant program awards one or two-year grants to young investigators, physician residents, and clinicians who are interested in studying SYNGAP1. SRF grants are intended to help researchers explore novel ideas and answer questions related to the clinical aspects, therapies and/or genetic causes of SYNGAP1. SRF is a member of the Personalized Medicine Coalition, COMBINEDbrain, Global Genes Foundation Alliance, Everylife Foundation Community Congress, Rare Epilepsy Network, Innovation and Value Initiative & the Epilepsy Leadership Council.

Visit SyngapResearchFund.org to learn more.

ABOUT RARE DISEASES MODELS & MECHANISMS NETWORK

The Rare Diseases: Models & Mechanisms Network has been established to catalyze connections between people discovering new genes in patients with rare diseases, and basic scientists who can analyze equivalent genes and pathways in model organisms. Catalyst Grants fund projects that will allow rapid confirmation of potentially disease-causing genes, and fuel pilot studies to improve understanding of how specific gene mutations cause disease. It is intended that collaborations across the Canadian biomedical community will expedite the understanding of disorders, enabling the design of new therapies to the ultimate benefit of those affected by rare diseases.

Visit rare-diseases-catalyst-network.ca/ to learn more.

Contact:

Peter Halliburton, SRF Development Director

peter@syngapresearchfund.org

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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SynGAP Research Fund announces grants to Dr. Kurt Hass, dr. Graziella DiCristo in partnership with Canada's rare diseases models and mechanisms...

About 1 in 44 children in the U.S. are diagnosed with autism spectrum disorder (ASD) by the age of 8, according to the 2018Centers for Disease Control and Prevention surveillance. How a childs DNA contributes to the development of ASD has been more of a mystery. Recently, clinicians and scientists have looked more closely at new, or de novo, DNA changes, meaning they only are present in affected individuals but not in the parents. Researchers have seen that these changes could be responsible for about 30% of ASD. However, which de novo variants play a role in causing ASD remains unknown.

Researchers at Baylor College of Medicine and Texas Childrens Hospital have taken a new approach to looking at de novo ASD genetic variants. In this multi-institutional study published in the journalCell Reports, they applied sophisticated genetic strategies in laboratory fruit flies to determine the functional consequences of de novo variants identified in theSimons Simplex Collection (SSC), which includes approximately 2,600 families affected by autism spectrum disorder. Surprisingly, their work also allowed them to uncover a new form of rare disease due to a gene called GLRA2.

ASDs include complex neurodevelopmental conditions with impairments in social interaction, communication and restricted interests or repetitive behaviors. In the current study, we initiated our work based on information from a cohort of ASD patients in the SSC whose genomes and those of their families had been sequenced, said co-corresponding authorDr. Shinya Yamamoto, assistant professor ofmolecular and human geneticsandof neuroscienceat Baylor and investigator at theJan and Dan Duncan Neurological Research Instituteat Texas Childrens. Our first goal was to identify gene variants associated with ASD that had a detrimental effect.

The team worked with thefruit fly lab modelto determine the biological consequences of the ASDassociated variants. They selected 79 ASD variants in 74 genes identified in the SSC and studied the effect of each ASDlinked gene variant compared to the commonly found gene sequence (reference) as a control, from three different perspectives.

Co-first author,Dr. Paul Marcogliese,postdoctoral fellow in Dr. Hugo Bellens lab, coordinated the effort on knocking out the corresponding fly gene, and examining their biological functions and expression patterns within the nervous system. They then replaced the fly gene with the human gene variant identified in patients, or the reference sequence, and determined how it affected biological functions in the flies.

Working with fruit flies carrying either the reference human gene or the variant forms, co-first authorDr. Jonathan Andrews, postdoctoral fellow inDr. Michael Wanglers lab at Baylor, was the point person investigating how these gene variants affected fly behavior. As ASD patients exhibit patterns of repetitive behavior as well as changes in social interaction, he evaluated the effect of the patient variants on an array of social and non-social fly behaviors, such as courtship and grooming. Its interesting to see that manipulation of many of these genes also can cause behavioral changes in the flies, Andrews said. We found a number of human genes with ASD variants that altered behavior when expressed in flies, providing functional evidence that these have functional consequences.

The third approach involved overexpressing the genes of interest in different tissue types in fruit flies. Co-first authorsSamantha Dealand Michael Harnish, two graduate students in Baylors Graduate Programs inDevelopmental BiologyandGenetics and Genomics, respectively, working in Dr. Yamamotos lab, headed these studies. While some gene variants may lead to conditions because they produce defective proteins, others may lead to disease because they cause overabundance or aberrant function of a particular protein, which can disrupt biological processes. We investigated whether overexpressing gene variants found in individuals with ASD might explain the detrimental effect for some of these genes, Deal said.

Altogether, the team generated more than 300 fly strains in which they conducted functional studies of human gene variants associated with ASD. Their screen elucidated 30 ASD-linked variants with functional differences compared to the reference gene, which was about 40% of the genes for which they were able to perform a comparative functional assay.

Some of the variants we studied had functional consequences that were moderately or clearly predicted to be disruptive, but other variants were a surprise. Even the state-of-the-art computational programs couldnt predict they would have detrimental effects, said Yamamoto. This highlights the value of using multiple, complementary approaches to evaluate the functional consequences of genetic variants associated with ASD or other conditions in a living animal. Our fruit fly approach is a valuable tool to investigate the biological relevance of gene variants associated with disease.

In addition, the wealth of data generated by the researchers revealed gene variants not previously connected with other neurodevelopmental diseases and uncovered new aspects of the complexity of genetic diseases.

GLRA2 was one gene we specifically focused on to follow up,Dr. Ronit Marom, assistant professor of molecular and human genetics at Baylor and lead clinician of this work said. We identified 13 patients, five males and eight females, carrying rare variants of this X-linked gene that had not been established as a neurological disease gene before. Furthermore, males and females carried variants with different types of functional consequences and the spectrum of neurological characteristics among these 13 patients was different between the two groups. For instance, many of the boys carried loss of function variants and had ASD, while the girls did not. They mainly presented with developmental delay as the main characteristic of their condition, and carried gain of function variants.

The picture that emerges is that ASD may not be one disorder involving many genes. It may actually be hundreds of genetic disorders, like those caused by certain GLRA2 variants, said Wangler, assistant professor of molecular and human genetics at Baylor and co-corresponding author of the work. We think that this information is important to physicians seeing patients with ASD.

For a complete list of the contributors to this work, their affiliations and the financial support for this project, seethe publication.

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Fruit fly study uncovers functional significance of gene mutations associated with autism - Baylor College of Medicine News

The genetic factors that give sufferers of endometriosis a higher risk of ovarian cancer have been explained, and the connection could increase the chances of finding treatments for both.

Endometriosis where tissue similar to the lining of the womb grows outside the uterus is among the most under-diagnosed diseases in countries where healthcare is sufficient to identify other common conditions. On average, it takes women suffering from it seven years to get diagnosed, because so many doctors dismiss descriptions of horrifying period pain, nausea, and other symptoms produced when the cells respond to hormones as if they were where they should be. Indeed, it's apparently easier to get funding to study whether having endometriosis makes women more attractive to men than for research to treat its effects.

This neglect may not only leave women to suffer intense pelvic pain and potential infertility, but it could also risk their lives following evidence those with endometriosis also carry a slightly heightened risk of epithelial ovarian cancer. However, a new paper in Cell Reports Medicine offers hope that the link could be turned to the advantage of sufferers of both conditions.

Although rarely directly fatal, the paper notes endometriosis shares features with cancer, including metastatic-like behavior, tissue invasion, proliferation, angiogenesis [formation of blood vessels], and decreased apoptosis [normal cell death].

The authors studied the genomes of 25,000 sufferers of ovarian cancer and 15,000 people with endometriosis. Such large sample sizes allowed them to look for features unusually common in both groups.

Our research shows that individuals carrying certain genetic markers that predispose them to having endometriosis also have a higher risk of certain epithelial ovarian cancer subtypes, namely clear cell and endometrioid ovarian cancer, lead author Dr Sally Mortlock of the University of Queensland said in a statement.

Rather than a single common gene, the authors found 28 locations within the human genome associated with both conditions, with a shared underlying signal at 19 of them. Identification of those genes offers a set of targets for researchers to work on, either through gene therapy or by identifying the proteins the genes code for.

For the one in nine women with endometriosis, knowing they are also at extra risk of ovarian cancer could add anxiety to everything else they are going through. However, Mortlock notes the extra danger only applies to certain forms of ovarian cancer clear cell and endometrioid and consequently the extra risk is small.

Overall, studies have estimated that 1 in 76 women are at risk of developing ovarian cancer in their lifetime and having endometriosis increases this slightly to 1 in 55, so the overall risk is still very low, Mortlock said. A very weak correlation was also found with high-grade serous ovarian cancer.

The findings, therefore, could be more important for the research implications than what they say about an individual's personal danger.

Nevertheless, if the message of the connection to cancer sinks in, this might be one way to get more doctors to take patients seriously when they describe endometriosis symptoms, which would be significant indeed.

Continue reading here:
Genetic Connection Between Endometriosis and Ovarian Cancer Identified - IFLScience

A Yale Cancer Center research team has identified novel oncogenic gene fusions in lung and pancreatic cancer, as well as sarcoma. The fusions involve RASGRF1 (an activator of RAS signaling) and promote cellular changes leading to tumor development. The research is described online ahead of print in Clinical Cancer Research.

The research team studied 103 lung adenocarcinomas in the Yale Lung Cancer Biorepository collected from individuals with minimal smoking history to assess the frequency of known oncogenic mutations in these tumors and to identify potential new oncogenic alterations. The team performed whole-exome sequencing and RNA sequencing on a subset of these tumors at the Yale Center for Genome Analysis and identified an established oncogenic mutation in 98 of the 103 tumors.

Through further analysis of one of the tumors that lacked a known oncogenic alteration, they found a novel gene rearrangement causing a fusion between two genes called OCLN and RASGRF1.

Using public databases of sequenced human cancer cell lines and tumors, the team identified two similar RASGRF1 fusions in pancreatic cancer and in sarcoma and demonstrated that these three fusions turn on RAS signaling and have tumor-promoting properties in cells. The research findings were established in part with mouse models through a collaboration with the Yale Center for Precision Cancer Modeling. From a small molecule inhibitor screen performed at the Yale Center for Molecular Discovery, the research team determined that cells containing RASGRF1 fusions are sensitive to trametinib, a targeted therapy that blocks a pathway activated by RAS signaling.

Through the collaborative efforts of several Yale Cancer Center Shared Resources, we characterized a new class of oncogenic fusions. While these fusions are uncommon, they occur in several types of cancer and our findings suggest a potential treatment strategy for advanced tumors with these fusions, said Frederick Wilson, MD, PhD, Assistant Professor of Medicine (Medical Oncology) and senior author of the paper.

Funding for the study was provided by the Doris Duke Charitable Foundation, the National Institutes of Health, the Beatrice Kleinberg Neuwirth Fund at Yale Cancer Center, and the Robert M. Harris Fund for Lung Cancer Research at Yale Cancer Center. The Yale Lung Cancer Biorepository is supported by the Yale SPORE in Lung Cancer.

Additionally, the following Yale authors contributed to this study: Lisa Hunihan, Dejian Zhao, Heather Lazowski, Man Li, Yuping Qian, Laura Abriola, Yulia V. Surovtseva, Viswanathan Muthusamy, Lynn T. Tanoue, Bonnie E. Gould Rothberg, Kurt A. Schalper, and Roy S. Herbst.

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New Class of Oncogenic Fusions Revealed in Lung and Pancreatic Cancer - Yale School of Medicine

New research underscores the value of sharing genomic information to advance gene matching for diagnosis and discovery

GAITHERSBURG, Md., March 16, 2022 /PRNewswire/ -- GeneDx, Inc., a leader in genomic analysis, today announced newly published research demonstrating the value of data sharing and research participation on a platform that supports clinician connections to rapidly uncover new gene-disease relationships, an approach which has resulted in publication of more than 200 new associations.

The research, published in Human Mutation, details the results of GeneDx's contributions to GeneMatcher, a genomic database designed to enable connections between clinicians and researchers. Despite the rapid advances of genetic medicine in the last 15 years, expanding knowledge about the connections between genetic variation and human health remains a critical need. Through GeneDx's contributions, at least 200 new associations have been published in the past three years, reporting either new disease-gene relationships or expanded clinical information for known disease-causing genes. A systematic approach that includes identifying candidate genes observed at the company's laboratory, helping support clinician-led research and following through to publication has yielded an important platform for expanding understanding of the links between genes and health.

Further, participation in GeneMatcher has helped patients and their families find answers that otherwise may not have been possible, by connecting them with researchers and confirming disease-gene relationships. For patients facing rare diseases, resolving uncertain findings or identifying new relationships that can confirm a diagnosis may mean the difference between years of testing and receiving an accurate diagnosis.

"We often talk about the importance of genomic information for establishing a diagnosis and unlocking access to precision therapies for individual patients. Our experience with GeneMatcher shows that is just the first step in the value testing creates. Patients and clinicians who participate in research pay it forward by spurring new discoveries," said Paul Kruszka, M.D., chief medical officer at GeneDx. "With thousands of rare diseases impacting millions of patients, establishing an effective approach to speed up the identification of disease-gene relationships and putting that knowledge to work to help patients is critical."

GeneDx's database of more than 300,000 clinical exomes has been a major driver of discovery. This dataset, supported by carefully annotated and structured clinical information, powers a potent diagnosis and discovery engine. Today roughly one-quarter of the clinically actionable findings provided to patients come from discoveries first made at GeneDx.

About GeneDx

GeneDx, Inc. is a global leader in genomics, providing testing to patients and their families worldwide. Originally founded by scientists from the National Institutes of Health, GeneDx offers a world-renowned clinical genomics program with particular expertise in rare and ultra-rare genetic disorders. In addition to its market-leading exome sequencing service, GeneDx offers a suite of additional genetic testing services, including diagnostic testing for hereditary cancers, cardiac, mitochondrial, neurological disorders, prenatal diagnostics, and targeted variant testing. GeneDx is a subsidiary of BioReference Laboratories, Inc., a wholly owned subsidiary of OPKO Health, Inc. (NASDAQ: OPK). To learn more, please visit http://www.genedx.com.

CONTACT: Julie McKeough, [emailprotected]

SOURCE GeneDx, Inc.

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GeneDx Announces Discovery of 200 New and Expanded Genetic Conditions - PR Newswire

The etiology of acne is complex and multifactorial with genetics playing a large role in determining risk, particularly for those individuals with severe acne. The results of a recent study have further elucidated the genetics of acne and advanced the knowledge of the genetic basis of acne risk by identifying versions of the genes that are common among individuals who suffer from this very common inflammatory skin disorder.

It is estimated that more than 85% of teenagers are affected by acne to some degree, and up to 8% have been reported with severe disease, making acne the most prevalent skin disease worldwide. Depending on the severity of the disease, acne can significantly impact self-image and the quality of life (QOL). Major complications of acne include scarring as well as the, at times, significant psychosocial distress that can persist long after active lesions have disappeared.

Approximately 80% of a persons risk of suffering from severe acne can be explained by differences in their genetic makeup, said Miguel E. Rentera, PhD, senior research fellow, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia, and co-author of the study. It is not a single gene but rather variations across hundreds of genes in the genome that determine whether someone is likely to get acne or not, and the extent or severity of the condition.

Rentera and fellow colleagues recently performed a large meta-analysis of genome-wide association studies (GWAS) of acne undertaken in 9 independent cohorts compromising a total of 615,396 study participants. Of the participants, 20,165 were acne cases and 595,231 were controls, making it the largest study of its kind, with the aim of identifying specific genetic variants that are more common among people with moderate or severe acne relative to those who have mild or no acne. Fine-mapping and genome-wide analytical approaches were combined to gain insights into the underlying genes and pathways through which the associated loci contribute to disease susceptibility.

Researchers could identify 29 new genetic variants that are more common in individuals with acne, as well as confirm 14 of the 17 variants already known to be associated with the condition, raising the total number of known acne risk loci to 46. Results also exposed relationships between acne and other complex/common traits, including behavioral, hormonal, inflammatory, and psychiatric traits, as well as shared molecular basis between acne and Mendelian hair and skin disorders, including pustular psoriasis.

Fifteen of these loci have been reported to have an effect in European populations while the remaining 2 have been reported to have an effect in a Han Chinese population. This highlights the potential differences in the genetic architecture of acne between different ethnic populations, warranting further investigation in studies of diverse ancestry. According to Rentera, however, one of the main limitations is the lack of availability of cohorts or biobanks focused on diverse ancestries.

Our study results highlight possible molecular pathways that are implicated in acne, opening new avenues for fundamental research and development of therapeutic targets, Rentera said. Looking forward, we could apply this knowledge to do genetic tests of acne risk and identify those individuals who are likely to present with acne.

Novel research studies will need to be designed and performed to better understand the role of the newly identified acne genes and the mechanisms of action of these new variants need to be characterized and their potential as therapeutic targets to treat acne need to be assessed, he said.

According to Rentera, the estimation of individual genetic acne risk scores relative to the general population will be perhaps the most immediate application of the current study findings.

We demonstrated that it is possible to use a persons genetic information to estimate their genetic risk of developing acne based purely on which genetic variants they inherited from their parents, Rentera said. In the future, we will be able to identify those individuals who are at high-risk of acne many years before they even notice the first signs.

Finding genes implicated in acne is the first step toward patient stratification and personalized medicine. Although continued research has been inching closer towards personalized medicine on the genetic level, this fulfillment is likely a few years away. A clinicians treatment and management choices in the future could be informed by the genetic profile of each individual patient, Rentera said, however there is still much work to be done regarding characterizing the genetic basis of different acne types and treatment response across different life stages.

This research enables a much better understanding of the genetic basis of acne, and investigation of these variants further illustrates the shared biology processes with other skin and hair traits as well as a shared genetic etiology with other common diseases, Rentera said. However, identifying the relevant genes is not the end but rather the beginning of a journey of discovery.

This article was originally published by sister publication Dermatology Times.

Reference

Mitchell BL, Saklatvala JR, Dand N, et al.Genome-wide association meta-analysis identifies 29 new acne susceptibility loci.NatCommun. 2022 Feb 7;13(1):702. doi: 10.1038/s41467-022-28252-5.

Originally posted here:
Examining the genetics of acne - Contemporary Pediatrics

According to Alethea Gerding, Managing Editor, ASCPT, "The article has been downloaded more than 3,000 times"

These results have important clinical implications as more than 4.2 million people in the US are known to suffer from painful DPN and nearly 1.3 million patients are considered to be refractory, meaning currently available medications do not work for them (Painful Diabetic Neuropathy, GlobalData 2018).

Helixmith launched a second phase 3 trial for DPN, REGAiN-1A (VMDN-003-2), in the US and are targeting release of top line results by the end of 2022. The company is planning to start a third phase 3 for DPN in the second half of 2022.

Key points of the CTS paper

About Diabetic Peripheral Neuropathy

Painful DPN is a common and debilitating complication of diabetes mellitus that has a profound negative impact on quality of life, sleep, and mood. Current therapies are palliative and do not target the mechanisms underlying painful DPN. Moreover, symptomatic relief is often limited, and many patients with painful DPN still use opioids.

About Helixmith Co., Ltd.

Helixmith is a clinical-stage gene therapy companybased in Seoul and San Diego, developing new and innovative biopharmaceuticals to tackle previously untreated diseases. The company has an extensive gene therapypipeline, including a CAR-T program targeting several different types of solid cancers and an AAV vector program targeting neuromuscular diseases. Engensis (VM202), the most advanced pipeline candidate, is a plasmid DNA therapy being studied for diabetic peripheral neuropathy, diabetic foot ulcers, claudication, amyotrophic lateral sclerosis, coronary artery disease, and Charcot-Marie-Tooth disease. The company is listed on KOSDAQ.

SOURCE Helixmith USA Inc.

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Paper Reporting Results from Helixmith's Phase 3 Gene Therapy Trial for Painful Diabetic Neuropathy was One of the Top-10 Most-Downloaded Articles in...

CAMBRIDGE, Mass., March 16, 2022 /PRNewswire/ -- Alltrna, a Flagship Pioneering company unlocking transfer RNA (tRNA) biology and pioneering tRNA therapeutics to regulate the protein universe and resolve disease, today announced the formation of Alltrna's Scientific Advisory Board (SAB) with leading experts in RNA biology and therapeutics. The SAB will work closely with Alltrna's leadership team as they map tRNA biology to systematically design tRNA medicines and encode a completely new, unifying approach to treating both rare and common human diseases driven by shared genetic mutations.

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"We are honored to have these remarkable and accomplished scientific leaders join Alltrna's Scientific Advisory Board," said Lovisa Afzelius, Ph.D., Origination Partner at Flagship Pioneering and Founding CEO of Alltrna. "Each person has made significant contributions and pioneered breakthroughs in RNA research and therapeutics, and together, they will be a powerhouse of expertise and experience for Alltrna, as we leverage our deep understanding of tRNA biology and its diverse combinatorial modifications to systematically design, program, and deliver tRNAs to correct disease."

"I've been working closely with Alltrna over the past couple years as the team has built a truly remarkable platform to unlock the entire tRNA biology space with an unprecedented therapeutic opportunity to help millions of patients with both rare and common diseases," said Rachel Green, Ph.D., Chair of Alltrna's SAB. "I'm delighted that these world leaders in RNA biology and therapeutic development have joined Alltrna's SAB at this pivotal time in the company's growth and look forward to working together to help Alltrna realize the enormous potential of tRNA biology as a novel framework and source for new programmable medicines."

Alltrna Scientific Advisory Board Members

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Rachel Green, Ph.D., Chair, is an investigator at the Howard Hughes Medical Institute (HHMI) and a Bloomberg Distinguished Professor in the Department of Molecular Biology and Genetics at the Johns Hopkins University School of Medicine. During her doctoral research at Harvard Medical School, Dr. Green developed in vitro selection approaches that are broadly used for the analysis of functional RNAs in many systems. Her current research focuses on mechanisms of mRNA translation and its regulation. Dr. Green is an elected member of the American Academy of Arts and Sciences (AAAS) and the National Academy of Sciences (NAS). In addition to Alltrna, she serves on the SAB for Moderna and Initial Therapeutics.

Tracy Johnson, Ph.D., is a HHMI Professor and Dean of Life Sciences and Senior Associate Dean at the David Geffen School of Medicine at UCLA. She has more than 25 years of experience studying the biochemistry of RNA. Her laboratory utilizes a combination of molecular genetics, bioinformatic, and biochemical approaches to understand mechanisms of gene regulation, particularly RNA splicing and chromatin modification, and the intersection between these reactions. Dr. Johnson has received numerous awards, including the National Science Foundation's CAREER and PECASE awards and the 2022 Ruth Kirschstein Diversity in Science Award from the American Society for Biochemistry and Molecular Biology.

Anastasia Khvorova, Ph.D., is a Professor in the RNA Therapeutics Institute and Program in Molecular Medicine at the University of Massachusetts (UMass) Chan Medical School, where her lab develops novel approaches and solutions to understanding natural and therapeutic RNA trafficking and delivery. She founded the UMass Nucleic Acid Chemistry Core, the only nonprofit facility in North America capable of gram-scale synthesis of modified oligonucleotides. Prior to UMass, Dr. Khvorova served as Chief Scientific Officer at Dharmacon, ThermoFisher, and RXi Pharmaceuticals. She is inventor on more than 150 patents and 200 patent applications and has authored more than 50 peer-reviewed publications, defining the field of RNAi drug design and development.

Melissa Moore, Ph.D., is the Chief Scientific Officer, Scientific Affairs at Moderna, where she leads mRNA biology, delivery, and computation science research. Previously, she was a Professor of Biochemistry & Molecular Pharmacology and a HHMI Investigator at the UMass Chan Medical School, where she was instrumental in creating a faculty-led program to facilitate the translation of discoveries into drugs, products, technologies, and companies. Her 23-year career in academic research focused on the roles of RNA and RNA-protein complexes in regulating gene expression, and her research touched on many human diseases. Dr. Moore is an elected member of AAAS and NAS, and she received the RNA Society Lifetime Achievement Award in 2021.

About Alltrna

Alltrna unlocks tRNA biology to correct disease. The company's platform incorporates AI/ML tools to learn the tRNA language and deliver diverse programmable molecules with broad therapeutic potential. Alltrna has an unprecedented opportunity to advance a single tRNA medicine to unify treatment across a wide range of diseases with the same underlying genetic mutation. Alltrna was founded in 2018 by Flagship Pioneering. For more info, visit http://www.alltrna.com.

About Flagship Pioneering

Flagship Pioneering conceives, creates, resources, and develops first-in-category bioplatform companies to transform human health and sustainability. Since its launch in 2000, the firm has, through its Flagship Labs unit, applied its unique hypothesis-driven innovation process to originate and foster more than 100 scientific ventures, resulting in more than $140 billion in aggregate value. To date, Flagship has deployed over $2.6 billion in capital toward the founding and growth of its pioneering companies alongside more than $19 billion of follow-on investments from other institutions. The current Flagship ecosystem comprises 42 transformative companies, including Axcella Health (Nasdaq: AXLA), Codiak BioSciences (Nasdaq: CDAK), Denali Therapeutics (Nasdaq: DNLI), Evelo Biosciences (Nasdaq: EVLO), Foghorn Therapeutics (Nasdaq: FHTX), Indigo Ag, Kaleido Biosciences (Nasdaq: KLDO), Moderna (Nasdaq: MRNA), Omega Therapeutics (Nasdaq: OMGA), Rubius Therapeutics (Nasdaq: RUBY), Sana Biotechnology (Nasdaq: SANA), Seres Therapeutics (Nasdaq: MCRB), and Sigilon Therapeutics (Nasdaq: SGTX).

Media Contact for AlltrnaJessica Yingling, Ph.D., Little Dog Communications Inc., jessica@litldog.com, +1.858.344.8091

(PRNewsfoto/Alltrna)

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Alltrna Announces Formation of Scientific Advisory Board with World-Leading RNA Experts - Yahoo Finance