MDA5

BOSTON--(BUSINESS WIRE)-- #Biotech -- Odyssey Therapeutics, Inc. , a biotechnology company pioneering next-generation precision immunomodulators for inflammatory diseases, today announced the formation of its Scientific Advisory Board (SAB), which includes renowned experts in the fields of immunology and therapeutic development. The SAB will be chaired by Stephen Blacklow, M.D., Ph.D., who holds positions at Harvard Medical School and the Dana- Farber Cancer Institute and is a recognized drug discovery innovator. “The lens by which we evaluate therapeutic opportunities is supported by the profound knowledge of immune biology among our team and trusted advisors,” said Gary Glick, Ph.D., founder and CEO of Odyssey Therapeutics. “We are fortunate to work with a group of preeminent scientific minds and recognized drug hunters with extensive track records in developing molecules that have successfully translated from scientific hypothesis to clinical validation and regulatory success. We look forward to benefiting from their collective experience as we move our lead programs into the clinic and advance our earlier-stage pipeline.” Dr. Blacklow commented, “I am excited to work alongside Gary, my esteemed SAB members and the Odyssey team. Odyssey’s differentiated approach and dedication to advancing medicines for inflammatory disease is inspiring, and I look forward to contributing my expertise to help drive these groundbreaking programs forward.” Odyssey’s SAB is comprised of the following members: Dr. Blacklow, M.D., Ph.D., Gustavus Adolphus Pfeiffer Professor and Department Chair of Biological Chemistry and Molecular Pharmacology at Harvard Medical School, member of the Department of Cancer Biology at the Dana-Farber Cancer Institute: Dr. Blacklow is a globally recognized expert in signal transduction at the structural and molecular level. His research on the Notch pathway, a complex signaling pathway integral to immune cell function, has led to the development of multiple investigational therapies for hematologic malignancies, such as T cell acute lymphocytic leukemia. Of his many awards and affiliations, Dr. Blacklow received the National Cancer Institute’s prestigious Outstanding Investigator Award in 2017, and was elected to the Association of American Physicians in 2018 and the American Academy of Arts and Sciences in 2024. He received his M.D. and Ph.D. degrees from Harvard University. Robert Abraham, Ph.D., former Executive Vice President of Cancer Biology at Odyssey: Dr. Abraham previously served as Chief Scientific Officer at Vividion Therapeutics, which was acquired in August 2021 by Bayer for $2 billion. He has extensive experience in both the pharmaceutical industry and academia, including 10 years at Pfizer where he served as Senior Vice President and group head in Oncology Research and Development, with oversight of cancer drug discovery and early clinical development. He previously held roles at Duke University Medical Center, including an Endowed Chair in the Department of Cancer Biology. Throughout his career, he has made significant contributions to multiple research areas, including cell signaling, T lymphocyte biology, rapamycin pharmacology and mTOR functions, cancer metabolism and DNA damage responses. He received a B.S. in biology from Bucknell University and a Ph.D. in pharmacology from the University of Pittsburgh. Richard Flavell, Ph.D., F.R.S., Sterling Professor of Immunobiology, Yale School of Medicine, and Investigator, Howard Hughes Medical Institute: Dr. Flavell is a co-discoverer of introns in cellular genes, and his research focuses on the molecular and cellular mechanisms that govern immune responses, from the characterization of signal transduction pathways to the regulation of immune cell differentiation and activation. His work has been instrumental in identifying key components of the innate immune system, such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs), and activation of the innate immune system and inflammatory disease. He received his B.Sc. and Ph.D. in biochemistry from the University of Hull, England. Alexander (Sasha) Rudensky, Ph.D., Director, Ludwig Center for Cancer Immunotherapy, Tri-Institutional Professor at Memorial Sloan Kettering Cancer Center, The Rockefeller University and Cornell University, and Investigator, Howard Hughes Medical Institute: Dr. Rudensky’s research has defined regulatory T cells and the roles they play in autoimmunity, tolerance, allergic disease, infections and cancer. His current work addresses the molecular mechanisms underlying regulatory T cell activity, and the role these cells play in autoimmunity, tumor immunity and immunity to infections. He received his candidate of sciences degree from the Gabrichevsky Research Institute of Epidemiology and Microbiology, Moscow, and completed his postdoctoral work at the Yale School of Medicine. Ruslan Medzhitov, Ph.D., Sterling Professor, Yale University School of Medicine and Investigator, Howard Hughes Medical Institute: Dr. Medzhitov’s work has identified innate immune sensing pathways and established the principle of innate control of adaptive immunity. His current research is focused on inflammation biology, allergic diseases and evolutionary medicine. Dr. Medzhitov has been a recipient of numerous awards and honors, including the 2019 Dickson Prize in Medicine. He earned his Ph.D. from Moscow State University. Sun Hur, Ph.D., Professor at Harvard Medical School and Boston Children’s Hospital and Investigator, Howard Hughes Medical Institute: Dr. Hur’s work on the molecular mechanisms of how the immune system distinguishes between self and non-self-entities led to the discovery of MDA5 and its role in innate immunity, autoimmunity and autoinflammatory diseases. She is a past recipient of the Vilcek Prize for Creative Promise in Biomedical Science for her research on inflammatory and autoimmune diseases and experimental enzymology. She earned her B.Sc. from Ewha Womans University and her Ph.D. in physical chemistry from the University of California, Santa Barbara. Seth Masters, Ph.D., Centre Head, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research: Dr. Masters’ research on understanding the innate immune pathways that drive diseases led to the identification of the mechanisms by which NLRP1 mediates autoinflammatory disease. His current research explores how innate immune pathways contribute to inflammatory bowel disease, asthma, metabolic diseases and neurodegeneration. Dr. Masters obtained his B.Sc. in biochemistry from The University of Melbourne, Australia, and his Ph.D. in medical biology from the Walter and Eliza Hall Institute. Michael B. Yaffe, M.D., Ph.D., Professor of Biology and Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology: Dr. Yaffe’s research focuses on uncovering signaling pathways in cells that respond to stress, DNA damage and inflammatory cytokines and how the outputs of these pathways are integrated at the molecular and systems level to control the cell outcomes. Dr. Yaffe received his B.S. in materials science and engineering from Cornell University, M.D., Ph.D. degrees from Case Western Reserve University and advanced postdoctoral training with Prof. Lew Cantley at Harvard Medical School. About Odyssey Therapeutics Odyssey Therapeutics is a clinical-stage biotechnology company focused on discovering, developing and commercializing the next generation of inflammatory precision medicines. Since its founding in 2021, Odyssey has rapidly advanced a pipeline of clinical- and research-stage programs, leveraging the scientific expertise of its team of drug hunters and a comprehensive suite of tools to tackle drug targets with the greatest potential to benefit patients. Odyssey’s mission is to create extraordinary leaps in patient outcomes and change the standard of care for those living with serious inflammatory diseases. For more information, please visit odysseytx.com and follow Odyssey Therapeutics on X (formerly Twitter) and LinkedIn . Contacts Josh George jgeorge@spectrumscience.com 713-828-1913

A rare condition surged among previously unaffected groups of people during the COVID-19 pandemic and led to the deaths of nine patients, researchers say. The condition is a type of autoimmune response linked to the body immune system mistakenly attacking itself. Intriguingly, the system being attacked normally works as a sentinel or guard, whose job it is to detect invading viruses. It is mainly seen in East Asian women and girls and was very uncommon in the UK. But researchers who were examining data on MDA5 autoimmunity in Yorkshire during the pandemic noted an unprecedented 60 cases among mainly white men and women. Researchers investigating the increase in cases believe that exposure to the COVID-19 virus may trigger the condition, which causes distinctive skin rashes, pneumonia and interstitial lung disease, a rapidly progressing lung inflammation with damage which is often fatal. A rare condition surged among previously unaffected groups of people during the COVID-19 pandemic and led to the deaths of nine patients, researchers say. The condition is a type of autoimmune response linked to the body immune system mistakenly attacking itself. Intriguingly, the system being attacked normally works as a sentinel or guard, whose job it is to detect invading viruses. It is mainly seen in East Asian women and girls and was very uncommon in the UK. But researchers at the University of Leeds and Leeds Teaching Hospitals NHS trust, who were examining data on MDA5 autoimmunity in Yorkshire during the pandemic, noted an unprecedented 60 cases among mainly white men and women. Researchers investigating the increase in cases believe that exposure to the COVID-19 virus may trigger the condition, which causes distinctive skin rashes, pneumonia and interstitial lung disease, a rapidly progressing lung inflammation with damage which is often fatal. Principal Investigator Dennis McGonagle, Professor of Investigative Rheumatology in the University of Leeds' School of Medicine and Leeds Teaching Hospitals NHS Trust, said: "Whilst we very occasionally see this disease in the UK, this surge in cases was completely new and very different. "It is important that physicians understand the symptoms so that patients can be quickly referred for treatment and have the best chance of a rapid and full recovery. Lives could undoubtedly be saved but there is a great need for research to try and slow or stop the rapid lung progression that occurs in some patients." The research paper is published in The Lancet eBioMedicine. Viruses and autoimmune response The immune system contains a protein called MDA5, which helps detect RNA viruses like COVID-19. Normally, this protein helps trigger an immune response in the body, where more of the protein is produced to help fight off the virus. However, sometimes the immune system releases antibodies which mistakenly attack this protein, leading to MDA5 autoimmune diseases such as the rare disease described in this study. The exact cause is not well understood, but scientists believe the virus itself could trigger the response. Autoimmune diseases seen after viral infections have similar features, such as fatigue, joint pain and swelling, skin rashes and digestive issues. During the COVID-19 pandemic, physicians saw a rare condition in children called multisystem inflammatory syndrome in children (MIS-C) where there was no evidence of active viral infection of the lungs. This MIS-C syndrome affected multiple systems in the body, including the heart, kidneys, brain, skin, eyes, and digestive organs, but usually spared the lungs. The disease seen in Yorkshire was dubbed MIP-C (pronounced "mipsy") because of its similarities to MIS-C in that it occurred around the time of the pandemic but where active infection was usually absent. The 60 patients in the study presented at their GPs or to A&E with a range of symptoms including shortness of breath, muscle pain, rashes, and reduced blood flow to the fingers, known as Raynaud's disease. These symptoms are associated with autoimmune disease. The patients were referred to rheumatology specialists for further testing and all were diagnosed with the condition. Of the 60 patients, 35 had received COVID-19 vaccinations, and 15 had previously tested positive for COVID-19. However, patients were not systematically tested for COVID-19, and some may have been infected, but were asymptomatic at the time. Such cases could have developed MDA5 disease due to an overreaction of their immune system to minimal exposure to the virus. Twenty-five out of the 60 patients (41.7%) developed interstitial lung disease, and despite treatment with immunosuppressant medication, eight of those patients died. A ninth patient, who did not have interstitial lung disease, died from sepsis. To understand the increase in cases of this rare condition, researchers collected data on the number of these tests between January 2018 and December 2022, alongside data on COVID-19 infections and vaccination, and information about each patient's symptoms. Analysis showed that just six cases of the rare condition had been diagnosed between 2018 and 2019. However, in the 3 years after 60 new cases appeared, eight cases were diagnosed in 2020; 35 cases were diagnosed in 2021 and 17 cases were diagnosed in 2022. Very few cases have occurred since then. Patient demographics Patients were aged between 43 and 71 years, with 36 of them being female. Ethnicity: Researchers noted that there was a strong overlap in 2021 between vaccination rates in Yorkshire and the surge in MDA5 disease cases. This peak, though, also occurred shortly after a community wave of coronavirus infection occurred in late 2021. A smaller overlap was seen between confirmed COVID-19 infection and MDA5. However, it was interesting to note that almost half (42%) of patients were not documented to have been vaccinated against COVID-19 before they tested positive for MDA5. Four children who tested positive for MDA5 were unvaccinated, pointing to the idea of an overreacting immune response after exposure to a virus. Professor McGonagle said: "We know that vaccines can trigger an immune overreaction, but given that not all of these patients were vaccinated against COVID-19, and the increase in cases occurred when the COVID-19 virus was circulating in significant numbers, the evidence strongly suggests that the increase in cases of this rare disease is linked to exposure to the virus." The data was generated by Dr Paula David and Dr Gabriele DeMarco from the University of Leeds' School of Medicine and the Leeds Teaching Hospitals NHS Trust, with their Trust colleague Dr Khizer Iqbal. This work was done in collaboration with Dr Pradipta Ghosh and her team at the University of California, San Diego, who showed that the MDA5 protein was found in higher amounts in patients with COVID-19 and in patients with other diseases involving MDA5. They discovered that this increase was linked to an abnormal immune response that slows the virus's ability to multiply and spread. Additionally, they found that higher levels of the MDA5 protein were associated with increased levels of Interleukin-15, a protein that activates T-cells, or immune cells. This interaction could be contributing to the autoimmune response. The investigators say that doctors should be aware of their findings so that patients can be more quickly diagnosed and referred for treatment, which could help lessen lung damage and save lives. This is especially so in subjects with suspected pneumonia not getting better on therapy and where the rashes, muscle involvement and other disease features are absent. Dr Paula David, the first author of the paper, said: "We think that this large, unprecedented outbreak of MDA5 disease in Yorkshire will help advance the field to better appreciate the role between viruses and autoimmunity." Dr Saptarshi Sinha, the co-first author of the paper and the interim director of PreCSN, added: "Here at PreCSN, we enjoy the ability to help researchers such as the McGonagle group dive into big data and find patterns rapidly with precision that allows us to connect the dots. In this case, we are glad we could find a connection between a clinical presentation of autoimmune disease in the backdrop of COVID-19 at a molecular level."

An international collaboration recently uncovered a previously overlooked COVID-related syndrome: MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with COVID-19, or MIP-C for short. Pradipta Ghosh, M.D., sat down in her office at the University of California San Diego School of Medicine and considered a request from the other side of the world. Ghosh, a professor in the Departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, received an email from Dennis McGonagle, Ph.D., professor of investigative rheumatology at the University of Leeds in the United Kingdom. It began an international collaboration, one that uncovered a previously overlooked COVID-related syndrome and resulted in a paper in eBioMedicine, a journal published by The Lancet. McGonagle asked if she was interested in collaborating on a COVID-related mystery. "He told me they were seeing mild COVID cases," Ghosh said. "They had vaccinated around 90 percent of the Yorkshire population, but now they were seeing this very rare autoimmune disease called MDA5 -- autoantibody associated dermatomyositis (DM) in patients who may or may not have contracted COVID, or even remember if they were exposed to it." McGonagle told of patients with severe lung scarring, some of whom presented rheumatologic symptoms -- rashes, arthritis, muscle pain -- that often accompany interstitial lung disease. He was curious to know if there was a connection between MDA5-positive dermatomyositis and COVID-19. "DM is more common in individuals of Asian descent, particularly Japanese and Chinese," Ghosh said. "However, Dr. McGonagle was noting this explosive trend of cases in Caucasians." "But that's the least of the problem," Ghosh said. "Because he said, 'Oh, and by the way, some of these patients are progressing rapidly to death.'" Ghosh is the founding director of the Institute for Network Medicine at UC San Diego School of Medicine, home to the Center for Precision Computational Systems Network (PreCSN -- the computational pillar within the Institute for Network Medicine). PreCSN's signature asset is BoNE -- the Boolean Network Explorer, a powerful computational framework for extracting actionable insights from any form of big-data. "BoNE is designed to ignore factors that differentiate patients in a group while selectively identifying what is common (shared) across everybody in the group," Ghosh explained. Previous applications of BoNE allowed Ghosh and her team to identify other COVID-related lung and heart-afflicting syndromes in adults and children, respectively. As a rheumatologist, McGonagle specializes in inflammatory and autoimmune conditions. His expertise, combined with the computational power of the Institute for Network Medicine, proved to be an excellent collaboration for probing the post-pandemic upsurge in inflammatory and autoimmune diagnoses. Ghosh said that McGonagle's roster of patients, all within the U.K.'s National Health System (NHS), helped to facilitate the investigation. "The NHS has a centralized health care database with comprehensive medical records for a large population, making it easier to access and analyze health data for research purposes," Ghosh explained. Ghosh and McGonagle put together a team to probe what they found was indeed an entirely new syndrome. The UC San Diego team included Saptarshi Sinha, Ph.D., interim director of PreCSN, who was a co-first author on the paper, along with Paula David Ramos, M.D., who was conducting research fellowship in experimental rheumatology, at the Leeds Institute of Rheumatic and Musculoskeletal Medicine. The UC San Diego team also included two PreCSN-affiliated students, Ella McLaren, an undergraduate student and aspiring physician-scientist, and Sahar Taheri, a graduate student in the Jacobs School of Engineering Department of Computer Science and Engineering. The study began with McGonagle lab's detection of autoantibodies to MDA5 -- an RNA-sensing enzyme whose functions include detecting COVID-19 and other RNA viruses. A total of 25 patients from the group of 60 developed lung scarring, also known as interstitial lung disease. Ghosh noted that the lung scarring was bad enough to cause eight people in the group to die due to progressive fibrosis. She said that there are established clinical profiles of MDA5 autoimmune diseases. "But this was different," Ghosh said. "It was different in behavior and rate of progression -- and in the number of deaths." Ghosh and the UC San Diego team explored McGonagle's data with BoNE. They found that the patients who showed the highest level of MDA5 response also showed high levels of interleukin-15. "Interleukin-15 is a cytokine that can cause two major immune cell types," she explained. "These can push cells to the brink of exhaustion and create an immunologic phenotype that is very, very often seen as a hallmark of progressive interstitial lung disease, or fibrosis of the lung." BoNE allowed the team to establish the cause of the Yorkshire syndrome -- and pinpoint a specific single nucleotide polymorphism that is protective. By right of discovery, the group was able to give the condition a name: MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with COVID-19. It's MIP-C for short, "Pronounced 'mipsy,'" Ghosh said, adding that the name was coined to make a connection with MIS-C, a separate COVID-related condition of children. Ghosh said that it's extremely unlikely that MIP-C is confined to the United Kingdom. Reports of MIP-C symptoms are coming from all over the world. She said she hopes the team's identification of interleukin-15 as a causative link will jump start research into treatment. University of California San Diego co-authors are all noted above. This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes for Health (NIH) grant R01-AI155696 and pilot awards from the University of California Office of the President Research Grants Program Office (R00RG2628, R00RG2642 and R01RG3780) to Pradipta Ghosh. Saptarshi Sinha was supported in part by R01-AI141630 (to Pradipta Ghosh) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.