image:Veterinary epidemiologist Brian Vander Ley of the University of Nebraska-Lincoln's School of Veterinary Medicine and Biomedical Sciences, poses with Ginger, the first gene-edited cow resistant to bovine viral diarrheal virus (BVDV). view more

Credit: Craig Chandler|University Communication|University of Nebraska-Lincoln

Cattle worldwide face major health threats from a highly infectious viral disease that decades of vaccinations and other precautions have failed to contain. Federal, private-sector and Husker scientists are collaborating on a new line of defense, by producing a gene-edited calf resistant to the virus.

If follow-up research confirms its efficacy, the gene-editing approach offers long-term potential to reduce antimicrobial and antibiotic use in the cattle industry.

The bovine viral diarrhea virus (BVDV) devastates the bovine immune system and can cause severe respiratory and intestinal harm to infected beef and dairy cattle, said veterinary epidemiologist Brian Vander Ley, an associate professor in the University of Nebraska-Lincolns School of Veterinary Medicine and Biomedical Sciences.

In utero calves are especially vulnerable to infection. If they survive, they can remain infected for life, repeatedly spreading the virus to other cattle.

They show up as normal cattle but really, theyre shedding a tremendous amount of virus. Theyre the Typhoid Marys of BVDV spread, said Vander Ley, assistant director of UNLs Great Plains Veterinary Educational Center in Clay Center.

The cattle industry has vaccinated against the disease since the 1960s, but the highly mutable nature of BVDV and the emergence of highly virulent strains of BVDV contribute to limited success of present control programs, the Academy of Veterinary Consultants has stated.

Scientists identified the specific genetic structure associated with the disease earlier this century. A collaborative project involving scientists with the USDAs Agricultural Research Service and Acceligen, a Minnesota-based private company, used gene editing to change the small number of amino acids that lead to BVDV vulnerability, while keeping the rest of the protein, CD46, unchanged.

Our objective was to use gene-editing technology to slightly alter CD46 so it wouldn't bind the virus yet would retain all its normal bovine functions, said Aspen Workman, a scientist with ARS U.S. Meat Animal Research Center (USMARC) in Clay Center, Nebraska.

A gene-edited calf, named Ginger, was born on July 19, 2021, and was transported to UNL a week later for close monitoring by Vander Ley. Throughout, Ginger has remained a bright, healthy calf, normal both physically and behaviorally, which included a week with a BVDV-infected dairy calf that was shedding the virus in great volume.

The research findings will be published online May 9, by the PNAS Nexus open-access journal, a sibling publication to the Proceedings of the National Academy of Sciences. Workman is lead author.

Ginger is a Gir, a tropically adapted cattle breed used to develop Brahman cattle in North America. Follow-up research will require experimental replication in other cattle breeds. Ginger also will be monitored through pregnancy, if it occurs.

If the gene-editing approach proves viable, it could potentially reduce the cattle sectors use of antimicrobials, Vander Ley said.

The most successful version of the future that I can see is one where we don't have to deal with antimicrobial resistance because we just don't use that many antimicrobials, he said. That's better for everyone. That means that we have eliminated the cause of a lot of the antimicrobial use and we've eliminated that expense for livestock producers.

Michael Heaton, a USMARC researcher for the BVDV project, concurred. This line of research represents another opportunity to lessen the need for antibiotics in agriculture, he said.

In addition to Vander Ley, Workman and Heaton, other study coauthors are Erin E. Jobman (Great Plains Veterinary Educational Center); Gregory P. Harhay (USMARC); private-sector scientists Tad S. Sonstegard, Dennis A. Webster, Luke Sherry, Sabreena Larson, Daniel F. Carlson and Jonathan Bostrom; and Theodore S. Kalbfleisch with the University of Kentucky.

Experimental study

Animals

First gene-edited calf with reduced susceptibility to a major viral pathogen

9-May-2023

Co-authors D.W., J.B. and D.C. are full-time employees of Recombinetics, Inc. S.L. and T.S. are employees of Acceligen, a wholly owned subsidiary of Recombinetics, Inc. Recombinetics, Inc., is a company that commercializes animal gene editing and associated applied technologies for biomedical research, regenerative medicine and animal agriculture. There are no patents to declare, and the interests do not alter the authors' adherence to all the journal's policies on sharing data and materials published herein.

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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Gene-edited calf may reduce reliance on antimicrobials against ... - EurekAlert

The Office of Innovation and Entrepreneurships 2023 Celebration of Innovation on April 25, at the Petersen Events Centers Campus View Club recognizes Pitt innovators and regional businesses who are creating solutions to difficult societal problems and serving unmet needs through the commercialization of their innovations.

This event included seven special awards; an innovation showcase where nine emerging Pitt innovation teams in the early stages of commercialization were on hand to share their progress on the path from the classroom or lab to market; and recognition of all faculty and students who submitted an invention disclosure, were issued a U.S. patent or had their innovation licensed.

The culture of innovation and entrepreneurship at Pitt is getting stronger all the time, said Evan Facher, vice chancellor for innovation and entrepreneurship and associate dean of commercial translation at the School of Medicine. This years Celebration of Innovation, in-person again for the first time since 2019, is our opportunity to bring our innovation and entrepreneurship community together to celebrate our successes, while recognizing several individuals and companies that are improving lives through their innovations.

The Innovation Award winners are:

Marlin Mickle Outstanding Innovator Award: William Wagner, director of the McGowan Institute for Regenerative Medicine as well as distinguished professor of surgery, chemical engineering and bioengineering

The Marlin Mickle Outstanding Innovator Award is presented to a Pitt faculty member who has achieved a sustained commitment to innovation throughout a distinguished career. Wagners research interests are generally in cardiovascular engineering, with projects that address medical device biocompatibility and design, hypothesis-driven biomaterials development and tissue engineering. His research has generated nearly 50 issued patents and patent filings that have resulted in significant licensing activity and the formation of three startup companies. Under his leadership, the McGowan Institute has grown into the most prolific research institutes at Pitt in terms of commercialization activity.

Emerging Innovator Award: Leah Byrne, assistant professor of ophthalmology at the School of Medicine

The Emerging Innovator Award is presented to an early-to-mid-career Pitt faculty who has demonstrated an extraordinary dedication to innovation commercialization. Byrnes research lab develops gene therapies for retinal disease. Byrnes lab engineers viral vectors with improved capabilities to deliver therapeutic genes to the retina that allow for increased precision of gene delivery and protein expression. In July 2022, the Swiss pharmaceutical company Roche partnered with Avista Therapeuticsa spinout based on Byrnes work and co-founded with Jos-Alain Sahel and Paul Sievingto further develop these therapies.

Student Innovator of the Year Award: Kunal Gandhi, a 2021 graduate of the University of Pittsburgh

Gandhi is CEO of APEX, which empowers clinicians to improve and expand access to musculoskeletal care using 3-D motion capture technology blending computer vision artificial intelligence with neuroscience to bridge in-person and virtual care. He leveraged the programs and resources of the Office of Innovation and Entrepreneurships Big Idea Center in each of his four years as an undergraduate to start on an entrepreneurial path after graduating.

James Chip Hanlon Volunteer Mentor of the Year Award: Jan Berkow, program manager for commercialization at the Pitt Center for Military Medicine Research

The Pitt Innovation Institute relies heavily on volunteer mentors to assist faculty and students interested in exploring the commercial potential of their innovations to navigate the often unfamiliar terrain of innovation commercialization. Berkow is responsible for bringing to market U.S. Department of Defense-funded advanced medical technologies. He previously led InteloMed Inc., a Pitt startup company, as co-founder and chief technology officer. For the past five years, he has served as a volunteer mentor on numerous Pitt innovation teams, helping to guide them through early commercialization exercises in customer discovery and value proposition development as part of the NSF I-Corps First Gear program, as well as assisting teams participating in the Michael G. Wells Student Healthcare Competition.

Startup of the Year: Apollo Neuroscience, Inc.

Apollo Neuroscience is a spinout from the University of Pittsburgh that began in 2018. The company has developed a wearable device and software platform technology that delivers patented vibration patterns, Vibes, that are scientifically shown to increase resilience, helping you to relax, sleep well, focus and stay energized by sending gentle sound waves to any location on the body. The Apollo Technology is based on the research of David Rabin and Greg Siegle from the Department of Psychiatry between 2014-2018. Kathryn Fantauzzi joined the team as an entrepreneurship mentor to help lead it to an award from the Innovation Institutes First Gear commercialization program. The team also received a top prize in the Michael G. Wells Student Healthcare Competition as well as the second-place prize in the inaugural Performance Innovation Tournament. The team placed as a finalist in the Pitt Innovation Challenge (PInCh) in 2016 sponsored by CTSI, only to receive the grand prize at PInCh 2017. Since spinning out in 2018, Apollo Neuroscience has successfully produced and marketed the Apollo wearable, selling more than 100,000 units to date. Apollo Neuroscience continues to be headquartered in Pittsburgh.

Small Business of the Year Award (Less than $1 million in revenue): Stories Like Me

Stories Like Me is an independently owned bookstore and community hub promoting equality, equity and inclusion. Its mission is to be the most comprehensive resource for diverse, accessible and empowered childrens literature and to share the stories of the world with a focus on generating empathy and peace through books. It recently opened a new physical bookstore at 4381 Murray Ave. in Pittsburghs Greenfield neighborhood.

Regional Business of the Year Award ($1 million+ in revenue): 84 Lumber

Founded in 1956 and headquartered in Eighty Four, Pennsylvania, 84 Lumber is the nations leading privately held supplier of building materials, manufactured components, and industry-leading services for single- and multifamily residences and commercial buildings. 84 Lumber is nationally certified through the Womens Business Enterprise National Council as a woman-owned and -operated business. It was named one of Americas largest private companies in 2018 by Forbes and a top workplace in the greater Pittsburgh region in 2018 by the Pittsburgh Post-Gazette.

Link:
Celebration of Innovation recognizes those making an impact - University Times

University of Minnesota researchers recently led successful efforts to build the first genome for Pallass cat (Otocolobus manul), a small wild cat native to central Asia known for its grumpy facial expression. The cat, which faces growing challenges from climate change, habitat fragmentation, and poaching, had no available genetic resources to help with conservation prior to this study.

The study, published in NAR Genomics and Bioinformatics, was led by Nicole Flack, a doctoral candidate in the College of Veterinary Medicine, along with Christopher Faulk, a professor in the College of Food, Agricultural, and Natural Resource Sciences.

The researchers used blood samples from Tater, a 6-year-old Pallass cat who lives at the Utica Zoo in New York, to construct a high-quality diploid nuclear genome assembly, a representative map of genes for the species.

The study results include confirmation that the Pallass cat is more closely related to certain wild cat species and less related to house cat species than some previous studies have suggested.

An allele-specific methylation analysis the first of its kind in cats also sheds light on how gene expression is regulated in mammals through a process called genomic imprinting. Mammals inherit two copies of each gene from their parents; usually these copies are equally active, but imprinted genes have chemical tags that turn off one copy. These findings pave the way to a deeper understanding of growth, development and hybridization among cat species, which could have important implications for genetic diversity and conservation.

The genomic resources the study produced provide a comprehensive genetic reference for conservation efforts working to track the health of wild populations and optimize breeding programs for cats in captivity.

Im hopeful our work will help with Pallass cat conservation. Genetic diversity is a key factor in the health and trajectory of animal populations, but its difficult to study without anything to compare to, said Flack. Our reference genome will be useful for monitoring the health of the Pallass cat population, both in captive breeding programs and in the wild.

These resources will enable future research not only on Pallass cat, but on the health, disease and physiology of house cats and other species even translational work to humans. This is particularly true of the assessment of allele-specific methylation, because imprinting is a unique feature of genes shared across mammals, and has significant implications for our understanding of human growth and development. But it has been chronically understudied because of the limitations of existing technology limitations that nanopore sequencing overcomes.

Our small team was able to provide Taters high-quality diploid cat genome including epigenetic information while using minimal financial and lab resources, said Faulk. We hope to serve as a model for conservation and sequencing projects from pathogens to people, especially by low-resource groups on limited budgets.

Project funding was provided by the United States Department of Agriculture National Institute of Food and Agriculture, the Norn Group, the National Institutes of Health, and the National Science Foundation.

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About the College of Veterinary MedicineThe University of Minnesota College of Veterinary Medicine affects the lives of animals and people every day through educational, research, service, and outreach programs. Established in 1947, the University of Minnesota College of Veterinary Medicine is Minnesotas only veterinary college. Fully accredited, the college has graduated over 4,000 veterinarians and hundreds of scientists. The college is also home to the Veterinary Medical Center, the Veterinary Diagnostic Laboratory, the Leatherdale Equine Center and The Raptor Center. Learn more at vetmed.umn.edu.

About the College of Food, Agricultural and Natural Resource Sciences The University of Minnesotas College of Food, Agricultural and Natural Resource Sciences (CFANS) strives to inspire minds, nourish people, and sustainably enhance the natural environment. CFANS has a legacy of innovation, bringing discoveries to life through science and educating the next generation of leaders. Every day, students, faculty, and researchers use science to address the grand challenges of the world today and in the future. CFANS offers an unparalleled expanse of experiential learning opportunities for students and the community, with 12 academic departments, 10 research and outreach centers across the state, the Minnesota Landscape Arboretum, the Bell Museum of Natural History, and dozens of interdisciplinary centers. Learn more at cfans.umn.edu.

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U of M researchers map the genome of the world's grumpiest cat - UMN News

This article has been reviewed according to ScienceX's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility:

by Chongqing Medical University

Credit: Gang Wang from Ruijin Hospital, affiliated to Shanghai Jiao Tong University School of Medicine

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting tens of millions of people worldwide, and it is the most common cause of dementia. Early-onset AD is typically associated with mutations in the genes APP, PSEN1, and PSEN2, leading to a more aggressive form of the disease with atypical symptoms. In contrast, the newly discovered "Shanghai APP" mutation has been linked to LOAD, which affects a larger population of AD patients.

In a study published in Genes & Diseases, researchers from Ruijin Hospital, affiliated to Shanghai Jiao Tong University School of Medicine and other three teams detected the Shanghai APP mutation in a Chinese patient who developed memory decline in his mid-70s. Neuroimaging techniques confirmed the presence of widespread amyloid deposition, a key hallmark of AD.

Using molecular dynamics simulation and in vitro experiments, the team found that the E674Q mutation led to increased processing of APP and production of amyloid , a toxic protein linked to AD. Additionally, the biochemical aggregation experiments suggested that the E674Q peptide exhibited higher aggregation than the wild-type peptide, especially the formation of filaments that hinged several fibrils.

To further investigate the mutation's effects in vivo, the researchers introduced the E674Q mutant APP gene into the hippocampi of two-month-old mice using adeno-associated virus (AAV) gene transfer. The study revealed that the E674Q mutation resulted in impaired learning behavior and increased pathological burden in the mouse model, demonstrating its pathogenic role in AD.

The E674Q substitution exhibited a strong amyloidogenic effect, and, to the researchers' knowledge, it is the only known pathogenic mutation within the amyloid processing sequence causing LOAD. This finding is significant, as it may open up new avenues for understanding the development of LOAD and lead to more effective treatments for patients suffering from this form of Alzheimer's disease.

The discovery of the novel Shanghai APP mutation provides a unique opportunity to delve deeper into the molecular mechanisms underlying LOAD. Further research into the effects of the E674Q mutation is essential to explore the potential development of targeted therapies or interventions that may slow or halt the progression of AD.

By understanding how this specific mutation contributes to the onset and progression of LOAD, scientists may be able to devise new strategies for preventing or treating this devastating disease, ultimately improving the quality of life for tens of millions of patients and their families.

More information: Yongfang Zhang et al, E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease, Genes & Diseases (2023). DOI: 10.1016/j.gendis.2023.02.051

Provided by Chongqing Medical University

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Researchers discover novel 'Shanghai APP' mutation in late-onset Alzheimer's disease - Medical Xpress

BioLegend Founder Gene Lay makes transformational gift to address steep rise in cancer and other immune-mediated and inflammatory diseases

BOSTON, May 10, 2023--(BUSINESS WIRE)--Brigham and Womens Hospital, a founding member of Mass General Brigham, today announces a historic $100 million gift from eminent biotechnology entrepreneur Gene Lay, MS, DVM, founder and CEO of BioLegend, Inc., through the Laygend Foundation. The landmark giftthe largest in the Brighams historywill establish The Gene Lay Institute of Immunology and Inflammation of Brigham and Womens Hospital, Massachusetts General Hospital (MGH), also a founding member of Mass General Brigham, and Harvard Medical School (HMS). Vijay Kuchroo, DVM, PhD, an immunologist and principal investigator at the Brigham, will serve as inaugural director of the institute, which will be located at and administered by the Brigham. Arlene Sharpe, MD, PhD, chair of the Department of Immunology at HMS, and Ramnik Xavier, MD, PhD, director of the Center for Computational and Integrative Biology at MGH, will serve as the institutes vice directors.

"I have always been fascinated by the immune systems ability to heal the body," says Lay. "And Ive had a longstanding relationship with and respect for the scientists in the Harvard medical community, who played an instrumental role in my career. With this gift, I am bringing together the best scientific minds I know to translate research discoveries into therapies for immune-mediated diseases rooted in chronic inflammation."

With a philanthropic investment of $100 million, the new institute will leverage the collective strengths of Boston and HMS-affiliated immunology and biomedical experts and their collaborations with some of the worlds most distinguished scientists. Kuchroo will lead day-to-day operations, convening core and affiliated faculty and trainees around three central platforms: basic science, translational science, and technology. The primary areas of research will include basic understanding of immune-mediated diseases, aging, and cancer and translation of this knowledge to the development of new immunotherapies. In addition, the Gene Lay Institute will provide substantial training opportunities for students and fellows to support immunology innovators of the future.

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"We are honored to receive this historic and visionary gift from Dr. Lay, who is deeply committed to solving an emerging trend in medicinethe rise of chronic inflammation associated with increased levels of disease and suffering," says Robert S.D. Higgins, MD, MSHA, president of the Brigham and executive vice president of Mass General Brigham. "This will amplify our ability to improve the quality of patients lives across the country and around the world. Were thrilled to be part of this pivotal moment in the field of medicine."

"During the past several decades, the astounding rise in inflammatory diseases has made it increasingly clear that chronic inflammation is a root cause of many diseasesnot only allergies and autoimmune diseases, but also cancer and neurodegenerative, cardiovascular, and metabolic diseases," says Kuchroo. "This transformative gift and investment will allow some of the best immunologists of our time to address this epidemic head-on and build new knowledge to promote basic understanding for preventing and treating immune-mediated diseases."

Adds George Q. Daley, MD, PhD, dean of HMS, "As weve seen with the COVID-19 pandemic, collaboration across institutions, disciplines, and modes of scientific inquiry is key to addressing our most confounding scientific and medical challenges. Were deeply grateful for this opportunity to convene the best immunologists in the world to bring solutions to patients and families."

Lay is the founder of San Diego-based BioLegend, now part of Revvity, Inc., which is a global life sciences and diagnostics company. BioLegend focuses on the development and production of high-quality antibodies, proteins, and assays for cellular immunity, inflammation, cancer, stem cells, and other reagents required for research and diagnosis. Since its founding in 2002, BioLegend has expanded its reach across the globe, with research and development facilities in Taiwan and Japan, as well as subsidiaries in Taiwan, Japan, China, Germany, the United Kingdom, the Netherlands, and France. Lay continues to give back to the scientific community while pursuing his dream of cultivating more expertise in Taiwan, the country where he was born.

About Brigham and Women's Hospital

Brigham and Womens Hospital is a founding member of Mass General Brigham and a teaching affiliate of Harvard Medical School. With nearly 1,000 inpatient beds, approximately 50,000 inpatient stays, and over 2.6 million outpatient encounters annually, clinicians across the Brigham provide compassionate, high-quality care in virtually every medical and surgical specialty to patients locally, regionally, nationally and around the world. An international leader in basic, clinical, and translational research, Brigham and Womens Hospital has nearly 5,000 scientists, including physician-investigators, renowned biomedical researchers and faculty supported by nearly $750 million in funding. The Brighams medical preeminence and service to the community dates to 1832, with the opening of the Boston Lying In, one of the nation's first maternity hospitals designed to care for women unable to afford in-home medical care. Its merger with the Free Hospital for Women resulted in the Boston Hospital for Women in 1966. In 1980, the Boston Hospital for Women, the Peter Bent Brigham Hospital and the Robert Breck Brigham Hospital officially merged to become Brigham and Womens Hospital. With nearly 21,000 employees across the Brigham family including the Brigham and Womens Physicians Organization and Brigham and Womens Faulkner Hospital that rich history is the foundation for our commitment to providing superb care for some of the most complex cases, pursuing breakthroughs in biomedical research, training the next generation of health care providers, and serving the local and global community.

View source version on businesswire.com: https://www.businesswire.com/news/home/20230510005276/en/

Contacts

Jessica Pastore 617-874-6346

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Historic $100 Million Gift to Brigham and Womens Hospital to Establish Institute of Immunology and Inflammation of the Brigham, Massachusetts General...

The dynamics of the cell and gene therapies market in rare disorders are anticipated to change as companies across the globe are thoroughly working toward developing new therapeutic options to treat a wide array of indications.

LAS VEGAS, May 9, 2023 /PRNewswire/ --DelveInsight's Cell and Gene Therapies in Rare Disorders Market Insights report includes a comprehensive understanding of current treatment practices, emerging cell and gene therapies for various rare disorders, market share of individual therapies, and current and forecasted market size from 2019 to 2032, segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan].

Key Takeaways from the Cell and Gene Therapies in Rare Disorders Market Report

Discover which therapies are expected to grab the major cell and gene therapies in rare disorders market share @ Cell and Gene Therapies in Rare Disorders Market Report

Cell and Gene Therapies in Rare Disorders Overview

Cell and gene therapies use genes and cells to treat disease. A gene is a unit of DNA containing genetic information passed down from generation to generation. The genome comprises all genes; genes may contain information on observable features such as height or eye color. Many genes contain instructions for RNA or protein molecules that are not visible from the outside but serve crucial tasks in the body's cells. Cells are the building blocks of plants and animals (including humans); they are small functional units that work together to generate organs and tissues. Cell and gene therapy technology is quickly evolving for many different diseases. However, cell and gene treatments are still experimental drugs, and much more study is required before many of these therapies are available to patients worldwide.

Cell and Gene Therapies in Rare Disorders Epidemiology Segmentation

DelveInsight estimates that there were approximately 900K prevalent cases of selected indications for cell and gene therapies in rare disorders in the 7MM in 2022.

As per our analysis, the highest prevalent cases from the selected indications for cell and gene therapies in rare disorders were for Retinitis Pigmentosa in the United States, whereas the least cases were reported for Hunter Syndrome in 2022.

The cell and gene therapies in rare disorders market reportproffers epidemiological analysis for the study period 20192032 in the 7MM segmented into:

Cell and Gene Therapies in Rare Disorders Market Insights

Numerous cell and gene therapies for rare diseases are currently approved in the 7MM, including retinitis pigmentosa (LUXTURNA), beta-thalassemia (ZYNTEGLO), epidermolysis bullosa (JACE), limbal stem cell deficiency (OCURAL), and many others. As per Delveinsight analysis, the total cell and gene therapies in rare disorders market size was around USD 1.5 billion in 2022. According to predictions, the United States will have the largest cell and gene therapies in rare disorders market. ZOLGENSMA produced the highest revenue of roughly USD 1 billion among the 7MM in 2022, while ROCTAVIAN is predicted to take the highest market share by 2032. ROCTAVIAN has received conditional approval in Europe for the treatment of severe hemophilia A. In addition to this approval, BioMarin Pharmaceutical is working to approve the drug in the United States, with a PDUFA target action date of June 30, 2023.

Hemophilia A is predicted to produce the most revenue among the selected indications by 2032, owing to the precedence of existing high treatment cost and expected high cost for emerging therapies along with significant residual unmet need. Gene treatments for Hemophilia A are estimated to earn around USD 6 billion in sales revenue by 2032 in the 7MM. The field of cell and gene therapies for rare indications is expected to rapidly expand in the coming years, as an increasing number of companies submit investigational new drug applications for these treatments each year, along with rising regulatory approval in the United States and Europe. In terms of manufacturing aspects of cell and gene therapies, there will be more competition for contract manufacturing businesses and pharmaceutical/biotechnology firms. The competition for contract manufacturing organization's production capacity will intensify as more companies enter the cell and gene therapy market, possibly driving up manufacturing costs. To ensure pharmaceutical/biotechnology firms can compete or obtain an advantage over competitors, companies may need to invest in manufacturing technologies or acquire companies with manufacturing expertise.

To know more about cell and gene therapies in rare disorders treatment guidelines, visit @ Cell and Gene Therapy Insights

Emerging Cell and Gene Therapies for Hemophilia A and Key Companies

Emerging Cell and Gene Therapies for Hemophilia B and Key Companies

Emerging Cell and Gene Therapies for Fabry Disease and Key Companies

Emerging Cell and Gene Therapies for Pompe Disease and Key Companies

Emerging Cell and Gene Therapies for Leber Hereditary Optic Neuropathy and Key Companies

Emerging Cell and Gene Therapies for Retinitis Pigmentosa and Key Companies

Emerging Cell and Gene Therapies for Hunter Syndrome and Key Companies

Emerging Cell and Gene Therapies for Batten Disease and Key Companies

Emerging Cell and Gene Therapies for Duchenne Muscular Dystrophy (DMD) and Key Companies

Emerging Cell and Gene Therapies for Amyotrophic Lateral Sclerosis (ALS) and Key Companies

Emerging Cell and Gene Therapies for Beta Thalassemia and Sickle Cell Anemia and Key Companies

Emerging Cell and Gene Therapies for Dystrophic Epidermolysis Bullosa and Key Companies

Emerging Cell and Gene Therapies for Ornithine Transcarbamylase Deficiency and Key Companies

Emerging Cell and Gene Therapies for Sanfilippo Syndrome Type A and Key Companies

Emerging Cell and Gene Therapies for Glycogen Storage Disease Type IA and Key Companies

Learn more about the FDA-approved cell and gene therapies for rare disorders @ Approved Cell and Gene Therapies in Rare Disorders Treatment

Cell and Gene Therapies in Rare Disorders Market Dynamics

The cell and gene therapies in rare disorders market is predicted to grow positively due to an increase in the approval of a growing number of gene therapies and their ease of adoption following approval, the ability to treat a wide range of conditions, an increase in the number of cases, an expected one-time dosing approach, and curative treatment options.

The approval of LIBMELDY, SKYSONA, HOLOCLAR, UPSTAZA, ROCTAVIAN, and other medicines has successfully created regulatory channels for the development of further cell and gene therapies. Companies around the world are working hard to develop new cell and gene therapies options to treat a wide range of indications, such as hemophilia A and B, lysosomal storage disorder (Fabry, Pompe Disease, Danon Disease, MPS I, MPS II, MPS III), neurological disorders (Batten, Parkinson), musculoskeletal disorders (DMD, myotubular myopathy), eye diseases (achromatopsia, limbal stem cell deficiency, retinitis pigmentosa, retinoschisis, age-related macular degeneration, Leber's hereditary optic neuropathy), and other indications such as diabetic macular edema, inborn metabolism disorder (Wilson's disease, Phenylketonuria, OTC deficiency/urea cycle disorders), dystrophic epidermolysis bullosa, gangliosidosis, and xerostomia.

Many diseases' treatment landscapes have drastically evolved in the last few years. Companies are now developing cell and gene therapies that will play an important role in the future, particularly in the treatment of rare genetic disorders. The process of defining ideal candidates for given gene therapy and cell therapy will have to wait for the enrolment and long-term follow-up of a sufficient number of study subjects to provide satisfactory clarity regarding its safety and efficacy. In conclusion, the future of cell and gene therapy looks optimistic. Several clinical trials have yielded favorable results in terms of safety and efficacy. The findings of these studies motivate additional research into many indications, and the current scenario predicts a positive shift in the cell and gene therapies in rare disorders market for the forecast period.

However, several factors may impede the growth of cell and gene therapies in rare disorders market in the coming years. Despite advances since the enactment of the Orphan Drug Act, people in the United States with rare diseases continue to face challenges to diagnosis, care, and treatment. Moreover, in Europe, a possible crisis with gene treatments for rare diseases is developing, and few companies have withdrawn the drug after failing to get reimbursement in the EU.

Report Metrics

Details

Study Period

20192032

Coverage

7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]

Base Year

2019

Cell and Gene Therapies in Rare Disorders Market CAGR

35.8%

Cell and Gene Therapies in Rare Disorders Market Size in 2022

USD 1.5 Billion

Key Cell and Gene Therapies in Rare Disorders Companies

Roche, Freeline Therapeutics, Spark Therapeutics, Astellas Gene Therapies, Actus Therapeutics, GenSight Biologics, Coave Therapeutics, Johnson & Johnson, MeiraGTx, Applied Genetic Technologies Corporation, GenSight Biologics, Nanoscope Therapeutics, 4D Molecular Therapeutics, Ocugen, jCyte, ReNeuron, REGENXBIO, Amicus Therapeutics, Pfizer, Sarepta Therapeutics, Capricor Therapeutics, Nippon Shinyaku, Brainstorm Cell Therapeutics, CRISPR Therapeutics, Vertex Pharmaceuticals, Editas Medicine, Sangamo Therapeutics, Krystal Biotech, Abeona Therapeutics, Castle Creek Biosciences, Holostem Terapie Avanzate S.r.l., RHEACELL, Ishin Pharma, Anterogen, Ultragenyx Pharmaceutical, and others

Key Pipeline Cell and Gene Therapies in Rare Disorders Therapies

Giroctocogene fitelparvovec, Dirloctocogene samoparvovec, Fidanacogene elaparvovec, Verbrinacogene setparvovec (FLT-180a), FLT190, Isaralgagene civaparvovec (ST-920), 4D-310, SPK-3006, AT845, ACTUS-101, LUMEVOQ (lenadogene nolparvovec), CTx-PDE6b, Botaretigene sparoparvovec, ATGC-501 (laruparetigene zosaparvovec), GS030, MCO-010 (sonpiretigene isteparvovec), 4D-125, OCU400, jCell, RGX-121, AT-GTX-502 (scAAV9.P546.CLN3), PF-06939926, SRP-9001, CAP-1002, NurOwn (MSC-NTF cells), Exagamglogene autotemcel, EDIT-301, BIVV003, VYJUVEK (beremagene geperpavec), EB-101, D-Fi (dabocemagene autoficel), RV-LAMB3-transduced epidermal stem cells, Allogeneic ABCB5-positive Stem Cells, ISN001, ALLO-ASC-SHEET, DTX301, UX111 (ABO-102), DTX401 (AAV8G6PC), and others

Scope of the Cell and Gene Therapies in Rare Disorders Market Report

Discover more about cell and gene therapies for rare disorders in development @ Cell and Gene Therapy Clinical Trials

Table of Contents

1

Cell and Gene Therapies in Rare Disorders Market Key Insights

2

Cell and Gene Therapies in Rare Disorders Market Report Introduction

3

Cell and Gene Therapies in Rare Disorders Market Key Highlights from Report

4

Executive Summary of Cell and Gene Therapies in Rare Disorders

5

Key Events: Cell and Gene Therapies in Rare Disorders

6

Cell and Gene Therapies in Rare Disorders Epidemiology and Market Forecast Methodology

7

Cell and Gene Therapies in Rare Disorders Market Overview at a Glance in the 7MM

8

Disease Background and Overview of Cell and Gene Therapies in Rare Disorders

9

Epidemiology and Patient Population

10

Marketed Cell and Gene Therapies in Rare Disorders

10.1

Key Competitors in Cell and Gene Therapies in Rare Disorders

10.2

Hemophilia A

10.2.1

ROCTAVIAN (valoctocogene roxaparvovec): BioMarin Pharmaceutical

10.3

Hemophilia B

10.3.1

HEMGENIX (etranacogene dezaparvovec): CSL Behring/uniQure

10.4

Retinitis Pigmentosa

10.4.1

LUXTURNA: Sparks Therapeutics (a company of Roche)/ Novartis

10.5

Spinal Muscular Atrophy (SMA)

10.5.1

ZOLGENSMA (onasemnogene abeparvovec-xioi): Novartis (AveXis)

10.6

Metachromatic Leukodystrophy (MLD)

10.6.1

LIBMELDY (atidarsagene autotemcel): Orchard Therapeutics

10.7

Limbal Stem Cell Deficiency

10.7.1

HOLOCLAR (Autologous human corneal epithelial cells containing stem cells): Holostem Terapie Avanzate S.r.l.

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Significant Positive Shift in the Cell and Gene Therapies in Rare ... - PR Newswire

Recently published in The New England Journal of Medicine, new findings from the SELECT2 trial (NCT03876457), a phase 3 international, randomized, open-label clinical trial, showed endovascular thrombectomy (EVT) resulted in better functional outcomes than medical care among patients with large ischemic strokes 24 hours after onset.1 These results provide evidence of the efficacy and safety of endovascular thrombectomy in patients with large ischemic strokes, which has been carried out in limited populations to date.

In favor of EVT, the generalized odds ratio for a shift in the distribution of modified Rankin scale (mRS) scores toward better outcomes was 1.51 (95% CI, 1.20-1.89; P <.001). Notably, a total of 20% of the patients in the EVT group and 7% in the medical-care group had functional independence (RR, 2.97; 95% CI, 1.60-5.51).

These findings were also presented as an oral presentation in the clinical trials plenary session at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, by lead author Amrou Sarraj, MD, director of the Cerebrovascular Center and Comprehensive Stroke Center at University Hospitals Cleveland Medical Center. The session covered the latest clinical trial results that impact the landscape of patient care in all the neurology subspecialities.2

Between September 2019 and September 2022, at the time the trial was stopped, 958 patients had been screened, and among those, 352 were eligible and enrolled. The trial included patients with stroke because of occlusion of the internal carotid artery or the first segment of the middle cerebral artery, and assessed EVT in the time span of 24 hours after onset. The patients enrolled had a large ischemic-core volume, defined by the Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0- 10, with lower scores indicating larger infarction) or at least 50 mL of a core volume on computed tomography perfusion or diffusion-weighted MRI.

Patients were assigned on a 1:1 ratio to either the EVT plus medical care group (n = 178) or the medical care alone group (n = 174). The mRS score at 90 days (range, 0-6, with higher scores indicating greater disability) was the primary outcome, and functional independence was the secondary outcome.

Among both groups, mortality was similar. Arterial access-site complications occurred in 5 patients, dissection in 10 patients, cerebral-vessel perforation in 7 patients, and transient vasospasm in 11 patients, all of whom were in the EVT group. One patient in the EVT group and 2 patients in the medical-care group experienced symptomatic intracranial hemorrhage.

Limitations of the trial include its early termination and the smaller than anticipated sample size. Although treatment was open label, the outcome assessment was conducted by assessors who were unaware of trial-group assignments. In addition, some patients enrolled had lower ischemic-core volumes than intended for enrollment and only approximately 20% of patients received intravenous thrombolytic agents before randomization.

Previous coverage of SELECT2 identified no safety concerns during a review of 90-day outcomes for the first 200 included participants.3 Findings from that analysis were presented at the 2022 International Stroke Conference (ISC) February 9-11, in New Orleans, Louisiana, by Sarraj. In the analysis, 200 patients were enrolled in the phase 3 study, 100 patients randomized received EVT and 100 were randomized to medical management (MM).

In the data presented at ISC 2023, participants in the EVT group had a median age of 66.5 years (IQR, 58.5-75) and those in the MM group had a median age of 67.5 (IQR, 59-76). Presentation National Institutes of Health Stroke Scale (NIHSS) scores were similar, averaging 19 (IQR, 15-23) for the EVT group and 19 (IQR, 15-23) in the MM group, as was time from stroke onset to randomization, averaging 9.3 hours (IQR, 5.0-15.25) for the EVT group and 9.9 hours (IQR, 5.95-15.9) for the MM group, and physician read CV Alberta Stroke Program Early CT Scores (ASPECTS), at 4 (IQR, 4-5) for the EVT group and 4 (IQR, 4-5) for the MM group. Overall, 176 patients had NCCT ASPECTS between 3-5, with a median ischemic core of 72 mL (IQR, 38.5-108.5). A total of 145 patients had an ischemic core of 50 mL, with a median ischemic core of 94 (IQR, 72-138).

Click here for more coverage of AAN 2023.

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Endovascular Thrombectomy Shows Better Functional Outcomes ... - Neurology Live

People on the Move is a rundown of recent hirings, promotions, appointments and other notable movements by professionals in the state. If youre interested in submitting an entry, please contact news@delawarebusinesstimes.com.

U.S. Senator Tom Carper (D-Del.) was named to the National Advisory Board for President Joe Bidens re-election campaign. The National Advisory Board is a select group of national Democratic leaders who will serve as the primary surrogates for the Democratic National Committee and Biden-Harris campaign in 2023 and 2024.

U.S. Senator Tom Carper (D-Delaware)

Im excited to join President Bidens national advisory board to stand beside my good friend Joe throughout his re-election campaign. Since they took office, President Biden and Vice President Harris have been fighting for everyday Americans and to protect our freedoms,Senator Tom Carper said in a statement. President Biden ran for the presidency in 2020 because he believed that we were in a battle for the soul of this nation and we still are. I encourage all Delawareans to join me in supporting the Biden-Harris campaign so we can all come together to help Joe and Kamala finish the job.

The stakes of this election couldnt be higher, President Joe Biden said. Our freedom and democracy are on the line. Im grateful to this group of diverse and dynamic leaders who will help us win the battle for the soul of America and finish the job for the American people.

Gawthrop Greenwood partner Carl W. Heckert has been elected secretary of the Delaware State Bar Associations Family Law Section during the esteemed organizations 100th anniversary year.

Heckert, who has more than 25 years of experiencepracticing family law in Delaware, has been a member of the Delaware State Bar Association since 1992 and will serve for the 2023-2024 section year.

Carl Heckert | PHOTO COURTESY OF GAWTHROP

Heckert is a member of theFamily Law Departmentin Gawthrop Greenwood, PCs Greater Wilmington office in Greenville, litigating and mediating divorce. In 2019, he became a Certified Family Law Mediator in Delaware following the states inaugural certification program by the Family Court of the State of Delaware as well as the Delaware State Bar Association. A certified Delaware family law mediator is a neutral third party who is charged with preserving confidentiality while helping couples resolve issues more creatively and amicably than they can in court, including custody, visitation, child support, property division and alimony.

Heckert also draws on his more than 30 years of real estate experience to settle real estate disputes during divorce proceedings. In January, he presented a seminar on the topic for Delaware family law judges and practitioners of theMelson-Arsht Inns of Court. He has also led Continuing Legal Education courses in family law matters including custody, protection from abuse and representing an unwilling minor as a guardian-ad-litem. Heckert received his law degree fromWidener University School of Lawand holds a Bachelor of Science degree from theUniversity of Delaware.

Wilmington Trust announced the addition ofSuzanne Lane as the senior relationship executive.

Lane will focus on asset managers and financial institution relationships for the loan market solutions team, employing innovative solutions to help meet individual clients goals. Throughout her 25-year career in corporate trust and banking, she has taken numerous leadership positions on multiple finance and asset management teams.

Lane is a passionate advocate about empowering women in the financial services industry and has served as a mentor for many women as they start or build their careers. Prior to joining Wilmington Trust, Lane was a relationship lead for U.S. Banks Global Platinum Corporate Trust clientele.Previously, she was Chief of Staff for Relationship Management in the Shareowner Services division of BNY Mellon. She also has held roles at KPMG, AIB, and State Street Bank.

Lane has managed large client service teams both domestically and in Europe. She holds a bachelors degree in business administration from Northeastern University, and has earned the CPA, CFA and CAIA designations.

Allen Friedland, M.D., MACP, FAAP, has been recognized with the Dema C. Daley Founders Award for his national impact as an educator, innovator and leader in internal medicine.

Allen Friedland | PHOTO COURTESY OF CHRISTIANACARE

Given by the Alliance for Academic Internal Medicine, the award honors internal medicine doctors who have greatly influenced undergraduate and graduate medical education and the development of training programs in internal medicine.

Dr. Friedland has been a tireless advocate and innovator for internal medicine, medicine-pediatrics, and residency education over two decades, said Vinay Maheshwari, M.D., MHCDS, Hugh R. Sharp Jr., Chair of Medicine and physician executive of the Medical Group at ChristianaCare. He is a mentor to countless physicians across the country and beloved by those who have had the privilege of working alongside him. What is most evident about Dr. Friedland is how much he cares about those he has taught locally and nationally all of them will forever be a part of his family. This award is a testament to a lifetime career dedicated to graduate medical education.

Friedland is ChristianaCares section chief of Medicine-Pediatrics (Med-Peds) and has served as the director of ChristianaCares combined Internal Medicine-Pediatrics residency program for 25 years. He also teaches medical students at ChristianaCare, which is a branch campus of Sidney Kimmel Medical College at Thomas Jefferson University and Philadelphia College of Osteopathic Medicine.

His accomplishments include:

Amanda Hewes, MS, education program manager at ChristianaCares Gene Editing Institute, has been named one of the 2023 Outstanding Delaware Women in STEM by Million Women Mentors, an international movement dedicated to encouraging girls and women to pursue careers in science, technology, engineering and math (STEM).

Amanda Hewes | PHOTO COURTESY OF CHRISTIANACARE

Hewes selection spotlights her dedication to engaging young people in the science of gene editing by introducing the Gene Editing Institutes CRISPR in a BoxTM educational toolkit into classrooms across Delaware and her commitment to bridging disparities in STEM education.

Im overjoyed to be honored among so many amazing women in this state, Hewes said. Its humbling to be considered and to stand alongside them. All of these women foster and lead dynamic communities of young women that inspire me every day. I hope that I can do the same by making young women in this state feel empowered through the work that I do.

Hewes joined ChristianaCares Gene Editing Institute in 2017 with a focus on expanding its CRISPR gene editing system in a cell-free environment. She was first author in a publication in Nature that established the highly innovative gene editing on a chip protocol that allowed CRISPR to edit DNA outside of the cell for the first time. This methodology enables researchers to take fragments of DNA extracted from human cells, place them in a test tube and precisely engineer multiple changes to the genetic code.

This gene editing system eventually led to the creation of the CRISPR in a Box toolkit. This innovative educational resource provides a way for students to learn about this exciting frontier of science through a hands-on exercise in which they use CRISPR gene editing to disrupt a synthetic gene within a plasmid. The simplicity of this experiment allowed for the reaction to be developed into a remarkable teaching tool that can be brought into most school laboratories containing basic laboratory equipment.

Once CRISPR in a Box was developed, Hewes recognized the potential it could have for high school and college students. She took on a new role as education program manager and expanded the Gene Editing 360 platform, which is the Gene Editing Institutes suite of educational tools for engaging students and the public.

Hewes was honored alongside 10 other women by Gov. John Carney, Lt. Gov. Bethany Hall-Long and others at the Delaware State House with the signing of a proclamation to declare March 24, 2023, as Delaware Women and Girls in STEM Day.

After 35 years of wearing Service Unlimited, Inc. (SUI) green, Safety Coordinator David Parag announced his retirement closing out a remarkable career serving the company and the people of New Castle, Delaware, and the surrounding areas.

Originally hired in the mid-1970s as an HVAC mechanic, Parag has served our customers in many different roles over three different terms. In his second term with the SUI family, Parag served as an electrician for our sister company, Electric Unlimited, Inc. (EUI), and ultimately led the company. Parag again returned to SUI as the Director of Construction Quality. He eventually added safety responsibilities to that role. Parag most recently was Safety Coordinator because of his passion for doing things the safest way rather than the fastest or easiest way.

Parag holds a Master License in both HVAC and Electrical. He has conducted countless training sessions, delivered tons of how-to documents, and mentored dozens of team members including Vice President Brian Martinenza. Parag will always be known around SUI for his oversized brain and his oversized heart because he knows virtually everything, and cares deeply about the people in his life. He enjoys being a catalyst for personal development and professional growth.

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People on the Move: May 12 - Delaware Business Times

image:A UNLV researcher holds a human brain model. view more

Credit: Josh Hawkins/UNLV

Could changing your diet play a role in slowing or even preventing the development of dementia? Were one step closer to finding out, thanks to a new UNLV study that bolsters the long-suspected link between gut health and Alzheimers disease.

The analysis led by a team of researchers with the Nevada Institute of Personalized Medicine (NIPM) at UNLV and published this spring in the Nature journalScientific Reports examined data from dozens of past studies into the belly-brain connection. The results? Theres a strong link between particular kinds of gut bacteria and Alzheimers disease.

Between 500 and 1,000 species of bacteria exist in the human gut at any one time, and the amount and diversity of these microorganisms can be influenced by genetics and diet.

The UNLV teams analysis found a significant correlation between 10 specific types of gut bacteria and the likelihood of developing Alzheimers disease. Six categories of bacteria Adlercreutzia, Eubacterium nodatum group, Eisenbergiella, Eubacterium fissicatena group, Gordonibacter,andPrevotella9 were identified as protective, and four types of bacteria Collinsella, Bacteroides, Lachnospira,andVeillonella were identified as a risk factor for Alzheimers disease.

Certain bacteria in humans guts can secrete acids and toxins that thin and seep through the intestinal lining, interact with theAPOE(a gene identified as a major risk factor for Alzheimers disease), and trigger a neuroinflammatory response affecting brain health and numerous immune functions, and potentially promoting development of the neurodegenerative disorder.

Researchers said their novel discovery of the distinct bacterial groups associated with Alzheimers disease provides new insights into the relationship between gut microbiota and the worlds most common form of dementia. The findings also advance scientists understanding of how an imbalance of that bacteria may play a role in the disorders development.

Most of the microorganisms in our intestines are considered good bacteria that promote health, but an imbalance of those bacteria can be toxic to a persons immune system and linked to various diseases, such as depression, heart disease, cancer, and Alzheimers disease, said UNLV research professorJingchun Chen. The take-home message here is that your genes not only determine whether you have a risk for a disease, but they can also influence the abundance of bacteria in your gut.

While their analysis established overarching categories of bacteria typically associated with Alzheimers disease, the UNLV team said further research is needed to drill down into the specific bacterial species that influence risk or protection.

The hope is to one day develop treatments that are customized for an individual patient and their genetic makeup, such as medications or lifestyle change. Studies have shown that changes in gut microbiome through probiotic use and dietary adjustments can positively impact the immune system, inflammation, and even brain function.

With more research it would be possible to identify a genetic trajectory that could point to a gut microbiome that would be more or less prone to developing diseases such as Alzheimers, said study lead author and UNLV graduate student Davis Cammann, but we also have to remember that the gut biome is influenced by many factors including lifestyle and diet.

Genetic correlations between Alzheimers disease and gut microbiome generawas published this spring inScientific Reports.

In addition to faculty, undergraduate, and graduate student researchers from NIPM, scientists from the UNLV College of Sciences, UNLV School of Dental Medicine, UNLV School of Integrated Health Sciences Department of Brain Health, Kirk Kerkorian School of Medicine at UNLV, Columbia University, and University of Texas Health Science Center at Houston contributed to the study.

Scientific Reports

Meta-analysis

Cells

Genetic correlations between Alzheimers disease and gut microbiome genera

31-Mar-2023

The authors declare no competing interests.

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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Brain-belly connection: gut health may influence likelihood of ... - EurekAlert

St. Jude Childrens Research Hospital scientist Madan Babu Mohan, Ph.D., Center of Excellence in Data-Driven Discovery director and member of the Department of Structural Biology, has been elected a Fellow of the Royal Society of London. The Royal Society is the oldest scientific academy in continuous existence.

Babu was selected to join the Royal Society for his pioneering data science-based strategies to reveal fundamental principles in biological systems. His scientific accomplishments include determining the molecular mechanisms governing G-protein-coupled receptor (GPCR) signaling, uncovering the roles of disordered protein regions in biology and disease, and establishing genome-scale principles of gene regulation.

One-third of all Food and Drug Administration-approved drugs target GPCRs, membrane proteins found on the surface of cells. Babus work has shown how genetic and isoform variability of GPCRs can influence drug responses. His most recent work investigated how GPCR selectivity for G-proteins is determined. Understanding this family of proteins is of tremendous interest to the development of novel therapeutics.

I am honored for our work to receive this recognition, Babu said. The science we have achieved is possible because of long-term support for fundamental research and the collaborative environment at St. Jude and the MRC Laboratory of Molecular Biology in Cambridge, England. I am grateful for the many contributions of my past and current colleagues, as well as my mentors and family.

Dr. Babus election to the Royal Society is well-earned, and we are all honored to call him a colleague, said James R. Downing, M.D., president and CEO of St. Jude. His investigations of GPCRs have the potential to have profound implications for pharmaceutical development. Through these discoveries, we can advance cures for pediatric cancer and other catastrophic diseases.

I am delighted to welcome our newest cohort of Fellows, said Sir Adrian Smith, President of the Royal Society. They are pioneering scientists and innovators from around the world who have confounded expectations and transformed our thinking.

Founded in the 1660s, the Royal Society is an independent scientific academy of the U.K. and the Commonwealth. Its Fellows have included many of the worlds most eminent scientists and technologists, representing a range of personalities, from Sir Isaac Newton and Benjamin Franklin to Dorothy Hodgkin and Robert Webster (St. Jude Infectious Diseases, emeritus).

This year sees 59 Fellows, 19 Foreign Members and two Honorary Fellows elected. Babus fellow U.S.-based new Fellows and Foreign Members include researchers at Google DeepMind, Harvard University, the Howard Hughes Medical Institute, the Institute for Advanced Study, Stanford University and the University of Chicago.

Babu joined the faculty of St. Jude in 2020, following a 14-year tenure as a program leader at the MRC Laboratory of Molecular Biology in Cambridge, England. He earned his Ph.D. in computational genomics from Cambridge University and his undergraduate degree from Anna University, Chennai, India. Babu completed a postdoctoral fellowship with the National Institutes of Health, Bethesda, Maryland.

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St. Jude scientist M. Madan Babu elected to the Royal Society of ... - St. Jude Children's Research Hospital

Patients cohort

Among consecutive patients who underwent BRCA tumour testing through ION Torrent-based sequencing between August 2017 and February 2022, we retrospectively selected 222 high-grade ovarian cancer (HGOC) patients with the following histological subtypes: 203 serous (HGSOC), seven endometrioid, five clear-cell and seven with mixed histotypes.

Since NGS BRCA1/2 tumour testing was not available before 2017 in our Institution, 19 of 222 subjects underwent germline testing before tumour sequencing based on personal (very early age at diagnosis/previous breast cancer) or family history. According to the workflow used by our Molecular Tumour Board (MTB), in 73 out of 203 patients with upfront tumour testing subsequently received genetic counselling, either for targeted germline sequencing of a tumour-detected PV or for large genomic rearrangement analysis14.

The Ethics committee of Fondazione IRCCS Istituto Nazionale dei Tumori of Milan approved the use of both clinical and molecular data collected by the MTB for clinical studies and granted exemption from requiring written consent for tumour genetic testing from the patients, as these analyses were carried out in the context of a diagnostic and care setting (Approval Number INT 227/20). All the probands who underwent germline testing were aged over 18 and provided signed informed consent for the use of their biological samples and data for both diagnostic and research purposes. All methods were carried out in accordance with relevant guidelines and with the ethical principles of the Declaration of Helsinki.

The BRCA1 and BRCA2 genes were assessed by in-house NGS testing using the Oncomine BRCA Research Assay (Thermo Fisher Scientific, Inc). This assay provided a 100% coverage of all BRCA1 and BRCA2 exons, with an average of 64 bases of intronic flanking sequences upstream and downstream of each exon. Five m sections from formalinfixed paraffin-embedded (FFPE) samples were manually microdissected to isolate the highest percentage of neoplastic cells. Genomic DNA was extracted with protease K (incubation ON at 55C) and quantified with Qubit dsDNA BR kit (Thermo Fisher Scientific, Inc). The libraries were prepared with the IonAmpliSeq Library kit 2.0 (Thermo Fisher Scientific, Inc) and quantified with Qubit dsDNA HS kit (Thermo Fisher Scientific, Inc) following the manufacturers instructions. The libraries are diluted to 25pm, pooled and loaded on the Ion Chef to perform emulsion PCR and chip loading on 318 v2 chips. Sequencing was performed on ION PGM, using the HI-Q view Chef kit, according to the manufacturers instructions. Data were processed using the Torrent Suite 5.12.3 (TS). The quality of sequencing output was first evaluated through the plugin Coverage Analysis on the TS. Only samples whose librarys uniformity and on-target values were at least 80% and with a medium coverage of 1500X were considered valid. SNV analysis was performed in duplicate: the first variant calling was generated by the Variant Caller plugin from the TS and the resulting VCF file was loaded in the Variant Effect Predictor Tool (Ensembl, Version GRCh37) for the variants annotation. To eliminate erroneous base calling, we set each variant coverage>40X, a variant frequency on each sample>2% and a quality value>30. Variants within homopolymer (HP) longer than eight bases and with strand bias80% were not reported. In the second analysis, the BAM files were automatically uploaded from the TS to the Ion Reporter Software (IR, version 5.6 to 5.16) and the variant calling was integrated into the analysis pipeline Oncomine BRCA Research Somatic318. The results of both analyses were manually compared. Each variant was displayed on IGV (ver. 2.3.97). Synonymous variants were filtered out, while the remaining variants were classified into pathogenicity classes according to the Evidence-based Network for the Interpretation of Mutant Alleles (ENIGMA) consortium guidelines (https://enigmaconsortium.org/). Our assay could not reliably detect large intragenic rearrangements.

Two EDTA tubes of peripheral blood samples were collected from each patient who performed genetic counselling and was eligible for germline testing, either for targeted sequencing of tumour-detected pathogenic/likely pathogenic variants or for the analysis of large genomic rearrangements in patients with no actionable variants detected at tumour testing. Whole blood DNA was isolated through the MagCore Super automatic workstation with the MagCore Genomic DNA Whole Blood Kit (Diatech LabLine SRL, Jesi, Italy). Targeted Sanger sequencing of tumour-detected BRCA1/2 PVs was performed on purified PCR products by using BigDye Terminator v.3.1 Cycle Sequencing kit (Thermo Fisher Scientific, Inc.) and run on 3730Xl DNA Analyzer (Applied Biosystems; Thermo Fisher Scientific, Inc.), after purification with Agencourt CleanSeq-Beckman Coulter. Sequences were analysed by Mutation Surveyor Software (v5.0.1; SoftGenetics, LLC., State College, PA, USA). Targeted sequencing results were confirmed on both blood aliquots collected from each patient. Variants of uncertain clinical significance identified at tumour testing were not systematically investigated at the germline level. Eligible probands, who resulted negative at tumour testing with the Oncomine BRCA assay, were analysed for large deletions and duplications of BRCA1 and BRCA2 on blood DNA with the SALSA MLPA kits P045 BRCA2/CHEK2 and P002 BRCA1 probe mix (MRC-Holland, Amsterdam, the Netherlands), following the manufacturers instructions. MLPA products were run on the 3730Xl DNA Analyzer (Applied Biosystems; Thermo Fisher Scientific, Inc.) with the Gene Mapper Module (Applied Biosystems; Thermo Fisher Scientific, Inc.). The results were analysed through the Gene Marker Software v2.7.0 (SoftGenetics, LLC, State College, PA, USA).

Based on previous observations on the performance at homopolymers of ion semiconductor sequencing techniques, we focussed our analysis on stretches of six or more identical bases since the calling accuracy has been consistently shown to dramatically drop beyond this length15,17,25,28,30. We thus selected all 29 homopolymeric regions exceeding five repetitions to be analysed within the coding regions of both genes, including five in BRCA1 and 24 in BRCA2. Since truncating variants beyond codon 3326 of BRCA2 are not classified as high-risk variants, homopolymers downstream of the residue c.9976 of BRCA2 were not included in the analysis (Table 2).

To overcome the limitations of the ION reporter software, which filters out most indels at homopolymeric regions, we manually visualised the BAM alignment files of the 222 patients at the 29 regions with the IGV software (ver. 2.3.97). The median depth of coverage of the regions of interest ranged from 1045 to 6989X. Each sample showed a variable frequency of sequence alterations (both insertions and deletions) at each region. We estimated the variant allele frequency (VAF) of insertions and deletions (indels) by calculating the ratios of the maximum inserted or deleted reads over the total reads at each homopolymer (Suppl. Table 1).

Since the VAF of indels at homopolymeric regions has, in general, a left-skewed distribution, we employed a modified version of the Cancer Outlier Profile Analysis (COPA) approach31, which consists in scaling the above-cited to a normal distribution and subsequently calculating the outliers that exceeded the mean+3 median-adjusted deviations (+3) threshold.

To validate the outliers, for each of the 29 regions, we further defined a threshold based on the normalized distributions (either for percentage of insertion or deletion) of a control population. Since both in ovarian and other BRCA-associated cancers the predominant second hit is most often represented by loss of heterozygosity (LOH), while a second point mutation is an extremely rare event32,33,34, we used as control population a cohort of 46 patients in which a non-homopolymeric PV (either somatic or germline) had been already identified.

To avoid potential selection bias, which would affect the estimated frequency of pathogenic variants occurring at homopolymeric regions in our cohort, we excluded from the analysis the 19 patients who underwent germline testing before tumour testing. This group also included two patients with germline-confirmed homopolymeric PVs who resulted negative at tumour testing.

Therefore, we applied the (+3) thresholds estimated on the control population to the normalized distributions of the study cohort, composed of 157 individuals with no evidence of pathogenic variants at tumour testing with ION Torrent. In addition, according with filtering criteria used in a previous study, which focused on germline variants29, we considered only homopolymeric indels with an absolute VAF above 15% and in any case higher than the maximum value of the control population at each homopolymeric region. Lastly, regions with a total read count of less than 100 were excluded from the analysis.

Targeted Sanger sequencing was performed on tumour DNA to confirm the occurrence of outlier homopolymeric indels selected by using the defined thresholds.

More:
Prevalence of BRCA homopolymeric indels in an ION Torrent-based ... - Nature.com

Its perhaps ironic then that ORourke, in sharing the story behind the research, is among those currently thinking aloud about the pros and cons of engineering dramatically longer lives.

The researcher said firmly, Theres a discussion around anti-aging therapeutics that society needs to have.

Scientists have known for more than a decade now that several genetic and biochemical pathways can either extend or shorten a persons life. The long answer to why the genome evolved this way is complex, ORourke said. The short answer resides in reproduction.

Nature cares about organisms becoming healthy reproductive adults, she said. But once we have produced as many babies as we are capable of, nature doesnt care about our health.

Should our muscles atrophy, or remain firm and tight? We can obviously improve our muscle tone by exercise, for example. But at some juncture, instructions meant to optimize development and survival earlier in life begin to tell the body to slow down. Obsolescence is in our genetic programming.

In that regard, our bodies are complex communication networks. The inputs and middle links in aging communication were identified prior to the UVA research. And acting on that accumulated knowledge, previous scientists indeed figured out ways to slow down, and even reverse, aging in animals such as lab mice.

But one reason you may not have heard about all the developments has been the ugly tradeoffs: compromised immunity, cancer.

The problem with playing around with many of the input and middle-link genes is that as they are such important players in the cell and control so many things it is very hard or even impossible to find a condition in which you can only get the good effects of changing their activities, ORourke explained.

In her attempt to solve this problem, ORourke assembled a Hoos-who of UVA scientists.

The team that yielded the revelatory research was led by biology graduate student Abbas Ghaddar and postdoctoral fellow Vinod Mony, with the contributions of graduate students Swarup Mishra, Elisa Enriquez-Hesles and Mary Kate Horak; undergraduate students Samuel Berhanu, Emma Harrison, James C. Johnson and Aaroh Patel; and aging expert Jeffrey S. Smith, a professor of biochemistry and molecular genetics.

Traditionally, worms have been associated with death. In science, however, worms in particular, roundworms have been responsible for some major health breakthroughs, winning Nobel Prizes in physiology and medicine (along with their scientists).

The type of roundworm ORourke and company used wasnt the parasitic type sometimes found in our pets, but rather C. elegans, which grows to about a millimeter long and is clear-bodied. As the first multicellular organism to have had its entire genome sequenced, the roundworm is transparent in more than one way. The creepy-crawly may seem far removed from us humans, but its chemical pathways are remarkably analogous.

Using the worm as a key model for this research, the team sought to decipher what happens at the end of those previously mentioned communication chains that control aging (as opposed to the inputs or middle links).

Specifically, ORourke wanted to find the molecular players most responsible for aging, which are those that break or repair cells, and by extension, tissues and organs. The thought was that by being at the end of the communication chain, playing around with the genes might mean fewer unwanted effects.

They set out by looking at biologys natural process of cellular cleanup and repair, called autophagy. The command to renew cells has long been thought to underlie longevity.

Autophagy is a process that clears the unwanted and recycles parts of the cells, ORourke said. When cell components go bad, they need to be disposed of. To this end, autophagy breaks them down to use the parts to make new cell components.

So autophagy was the main anti-aging candidate, in particular because we had already defined that the mid-link gene we were studying acted as a switch to turn autophagy on when animals were fasting, a dietary intervention that extends lifespan.

If their hypothesis was correct and autophagy was promoting longevity, then by stopping it, animals would not live longer.

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Thanks to UVA Research, You Might Live to 120. But Can Society ... - UVA Today

Why do humans have disease if they went through millions of years of evolution? Its a question Steven Gazal, PhD, assistant professor of population and public health sciences at the Keck School of Medicine of USC, hopes to answer.

Gazal is part of an international team of researchers who have become the first to precisely identify base pairs of the human genome that remained consistent over millions of years of mammalian evolution, and which play a crucial role in human disease. Thefindings werepublishedin a specialZoonomiaedition ofScience.

Gazal and his team analyzed the genomes of 240 mammals, including humans, zooming in with unprecedented resolution to compare DNA. They were able to identify base pairs that were constrained meaning they remained generally consistent across mammal species over the course of evolution. Individuals born with mutations on these genes may not have been as successful within their species or were otherwise not likely to pass down the genetic variation. We were able to identify where gene mutations are not tolerated in evolution, and we demonstrated that these mutations are significant when it comes to disease, explains Gazal.

The team found that3.3% of bases in the human genome are"significantly constrained,"including 57.6% of the coding bases that determine amino acid position, meaningthese bases had unusually few variants across species in the dataset. The most constrained base pairs in mammals were over seven times more likely to be causal forhuman disease and complex trait, and over 11 times more likely when researchers looked at the most constrained base pairs in primates alone.

Thedataset wasprovided bytheZoonomiaconsortium, whichaccording to the project website, "is applying advances inDNA sequencingtechnologies to understand how genomes generate the tremendous wealth of animaldiversity.Gazalgives credit to Zoonomia for making this type of data available to researchers and anticipates it will be widely used by human geneticists. Its a cheap resource togenerate, as opposed to datasets generated in human genetic studies, says Gazal.

His teams findings are a significant step forward, as Gazal notes, "we do not understand 99% of the human genome, so it is fundamental to understand which part has been constrained by evolution and is likely to have an impact on human phenotypes. Their discoveries and methods could become crucial tools for further research.

The next step for Gazal and his team is to repeat the process with a primate-only dataset. By restricting the subjects, they hope to focus on functions of DNA that appeared more recently in human evolution. We expect this to be even more useful in determining information on human disease, says Gazal.

Meta-analysis

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Leveraging base-pair mammalian constraint to understand genetic variation and human disease

28-Apr-2023

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USC researcher uses mammal DNA to zoom into the human ... - EurekAlert

There is no complete genetic explanation for why humans live longer than mice or why tortoises can live for a century. Looking for answers in long-lived animals genomes is tempting for researchers who want to figure out which genes extend lifespan.

I want to live as long as possible, said Stephen Treaster, a postdoctoral researcher at Boston Childrens Hospital. I want to see what technology and society looks like in 1000 years, ideallyhe said. Treaster used rockfish as an unlikely organism to explore the possibilities for longevity and uncovered two new pathways that appear connected to lifespan. He and his colleagues published their results in Science Advances(1).

For aging studies, researchers mostly use short-lived animals like mice, which live about three years, or Drosophila and Caenorhabditis elegans, which live for months or days (24). To make them live 10, 15, 20 percent longer, it doesn't necessarily apply to our end of the aging spectrum, said Treaster. Evolution has already solved the aging problem. There are individual species that can live hundreds and hundreds of years. My approach is to look at these exceptionally long-lived models.

Lifespan arises in different species from a complex network of genes and environmental interactions. Because of that complexity, it is difficult to look at the genetics of many model organisms and say for certain which genes contribute to that organisms lifespan. Fortunately, a natural evolutionary experiment on longevity exists. Rockfish are a family of common marine fish with worldwide distribution. Some species of rockfish live as little as 10 years while others can reach ages of 200 years or more. Since the rockfish clade emerged a relatively recent eight million years ago, there hasnt been time for rockfish to develop much genetic diversity.

The wide variety of lifespans in rockfish make them an interesting model for aging research.

credit: NOAA's National Ocean Service

The rockfishs nascent lineage is an analysts advantage. The wide variety of lifespans that different rockfish lineages exhibit can easily be pinned to genetic differences. Just as important, rockfish lifespans do not correlate with environmental conditions such as temperature or water depth, the kind of confounding effects that might make a genetic link to longevity in other animals less clear.

By analyzing genes related to aging that seemed to be evolutionarily selected across a variety of different rockfish species with varying lifespans, Treaster identified two different genetic pathways that seem to have evolved along with changes in lifespan.

The first pathway controls insulin signaling. Scientists know that insulin signaling affects aging and metabolism from past studies in other model organisms. On one hand, this is kind of a boring result, said Treaster. On the other hand, however, the fact that insulin signaling reappeared when analyzing rockfish seems to confirm the groups approach.

It was extremely clever analysis. It's not an easy analysis to do because the genomes of these [fish] are not well described.-Stephen Austad, University of Alabama

The other less well-known pathway they found is in the flavonoid signaling network. The flavonoid pathway is made up of proteins with activity modulated by flavonoid molecules, which are three-ring and 15-carbon structures common in plants (5).

None of the previous mouse or fly studies have pointed to the flavonoid network, said Steven Austad, an evolutionary biologist and aging researcher at the University of Alabama at Birmingham who was not involved in the study. It was extremely clever analysis. It's not an easy analysis to do because the genomes of these [fish] are not well described.

While Treaster is excited about identifying a possible new genetic link to lifespan, he emphasized that how exactly flavonoid pathway genes affect lifespan is not known. The next step is to play with these genes from rockfish to see if we can extend longevity in a conventional model. We're doing that right now. We are targeting these genes in zebrafish to see if we can extend lifespan, said Treaster. If that work confirms that flavonoids do directly alter lifespan, then Treaster hopes that scientists interested in aging-related diseases may explore the pathway for potential drug targets.

Austad isnt certain that identifying these genetic pathways to aging in fish will result in druggable targets in humans. He doubts that the insulin pathway, which has a demonstrated connection to longevity in flies and roundworms, can be connected to human lifespan. The evidence that that's a major player in human aging is relatively sparse, he said, noting that there havent been any human centenarians with identified novel mutations in the insulin signaling pathway.

Nevertheless, the publication gave him hope. This flavonoid network it's really a new thing and deserves investigation, he said.

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New genetic pathways involved in aging - Drug Discovery News