MDA5

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.

Company developing potent and selective small molecule inhibitors of XRN1, a compelling oncology target to address tumors with high interferon signaling Presentations at Triple Meeting also demonstrate progress for novel DHX9 and potentially first-in-class ADAR1 programs LEXINGTON, Mass., Oct. 10, 2023 /PRNewswire/ -- Accent Therapeutics, a biopharmaceutical company pioneering a new class of small molecule precision cancer therapies, today announced it will present data unveiling a novel, previously undisclosed program in two poster presentations at the 35th AACR-NCI-EORTC Symposium held October 11-15, 2023 in Boston, Massachusetts. The company will also present data supporting development of its ADAR1 and DHX9 programs in two additional poster presentations. 5′→3′ exoribonuclease 1 (XRN1) is an enzyme that degrades single- and double-stranded RNA, playing roles in extracellular mRNA turnover and innate immunity through prevention of dsRNA accumulation and subsequent MDA5 and PKR-mediated immune signaling. Accent has identified XRN1 as a key vulnerability for therapeutic targeting of tumors with elevated type I interferon signaling and is developing small molecule inhibitors of this compelling oncology target, for which there are none currently disclosed. Two of the company's presentations at the meeting describe the preclinical validation of XRN1 as an oncology target and the subsequent characterization of selective inhibitors of XRN1. XRN1 knockout resulted in cell death due to accumulation of dsRNA and downstream activation of the MDA5 and PKR innate immune pathways in cells with intrinsically elevated type I interferon signaling, but not in those with low interferon signaling. Accent has identified novel, potent, and selective allosteric inhibitors that bind XRN1 with nanomolar target affinity without binding to XRN2. "We are excited to share our progress advancing our portfolio and to introduce our XRN1 inhibitor program as a potentially impactful approach to helping cancer patients," said Robert Copeland, Ph.D., President and Chief Scientific Officer of Accent Therapeutics. "These data demonstrate the versatility and promise of pursuing critical intracellular dependences of cancer biology to identify novel oncology targets with the potential to benefit broad patient populations." ADAR1 has emerged as a promising, yet challenging-to-drug, oncology target for which inhibition has been shown to induce downstream immune activation and subsequent cell death in cancer cells with high intrinsic type 1 interferon signaling—a trait that 15-30% of primary tumors share. Accent will also present its innovative suite of in vitro and cellular assays that enable identification of small molecule inhibitors of ADAR1. The resulting compounds are shown to potently inhibit cell growth in a cancer cell line with high interferon type 1 signaling. The company's final presentation at the meeting will highlight its progress developing small molecule inhibitors of the novel oncology target DHX9, an RNA helicase that has been reported to play important roles in the maintenance of genomic stability in multiple cancer types. The presentation will demonstrate that DHX9 inhibition in microsatellite instable tumors exhibiting defective mismatch repair induces replication stress and subsequent cell death. The poster presentations will be archived on the Accent website following the meeting. Details for the presentations are as follows: Title: Exoribonuclease XRN1 is a Therapeutic Vulnerability in Tumors with Intrinsically Elevated Type I Interferon Signaling Abstract Number: A163 Session & Location: Poster Session A – Exhibit Hall D Session Date & Time: Thursday, October 12, 12:30 pm – 4:00 pm ET Presenter: Maureen M. Lynes, Ph.D. Title: Discovery of Small Molecule Inhibitors of ADAR1 Abstract Number: A170 Session & Location: Poster Session A – Exhibit Hall D Session Date & Time: Thursday, October 12, 12:30 pm – 4:00 pm ET Presenter: Shane M. Buker, Ph.D. Title: Characterization of Selective, Allosteric Inhibitors of Human XRN1 Abstract Number: B073 Session & Location: Poster Session B – Exhibit Hall D Session Date & Time: Friday, October 13, 12:30 pm – 4:00 pm ET Presenter: Gordon J. Lockbaum, Ph.D. Title: DHX9 Inhibition as a Novel Therapeutic Modality in Microsatellite Instable Colorectal Cancer Abstract Number: C087 Session & Location: Poster Session C – Exhibit Hall D Session Date & Time: Saturday, October 14, 12:30 pm – 4:00 pm ET Presenter: Jennifer Castro About XRN1 XRN1 is an RNA exonuclease that plays important roles in innate immunity by preventing double-stranded RNA (dsRNA) accumulation. Tumors with intrinsic type I interferon signaling are acutely sensitive to XRN1 loss, making it a strong oncology target. Inhibitors of XRN1 have potential for use as monotherapy and in combination with immuno-oncology therapeutics. Accent is applying structure-based design approaches to develop potent and selective small molecule inhibitors of XRN1 to address cancer indications with high unmet medical need. About ADAR1 Adenosine deaminase acting on RNA 1 (ADAR1) is an enzyme that edits double-stranded RNA (dsRNA) to prevent recognition and downstream immune signaling. In tumor cells with high interferon signaling, small molecule inhibitors of ADAR1 have been shown to induce selective cell killing and immune sensitization, making it a highly attractive target for monotherapy and combination approaches with immunotherapies, such as checkpoint inhibitors. Accent is developing ADAR1 targeted therapies to address many solid tumor indications with significant unmet need, including non-small cell lung cancer, triple-negative breast cancer, ovarian cancer, and head and neck squamous cell carcinomas. About DHX9 Accent's lead program is a first-in-class DHX9 inhibitor with the potential to address high unmet need indications that lack targeted therapies; these include colorectal, endometrial, gastric, and other high microsatellite instable (MSI-H) cancers. Several additional undisclosed cancer types representing large patient populations are also being explored based on their sensitivities to DHX9 inhibition. DHX9 is a DNA/RNA helicase that has been reported to play important roles in replication, transcription, translation, RNA splicing, RNA processing, and maintenance of genomic stability. Hence, this enzyme represents a compelling novel oncology target as inhibition of DHX9 exploits key tumor vulnerabilities, resulting in cancer-specific death. Accent is currently conducting IND-enabling studies evaluating its DHX9 inhibitor. About Accent Therapeutics Accent Therapeutics is pioneering a new class of small molecule precision cancer therapies targeting critical intracellular dependencies that span multiple types of cancer. Building upon industry-leading expertise in RNA-modifying proteins (RMPs) and the systematic mapping of both the RMP space and adjacent high-value areas for drug discovery, the company is building a flexible model that allows for a diversity of approaches to developing potentially transformative biomarker-driven cancer medicines. Accent's therapies are designed for both novel and known, but suboptimally-addressed, high-impact oncogenic targets with the potential to benefit large patient populations with significant unmet need. For more information on Accent's mission to translate extraordinary science into life-changing therapeutics for patients living with cancer, visit or follow us on LinkedIn. SOURCE Accent Therapeutics, Inc.