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These mutations lead to manifestations affecting neurodevelopment, bone and joint development, fibrosis and stenosis, immune responses, reproductive health, and cardiac function. The Myhre Syndrome Foundation (MSF) is a patient\u2010centered organization focused on accelerating drug discovery while supporting patients, prioritizing research targeting fibrosis\/stenosis and autism\/intellectual and developmental disabilities, the most significant burdens reported by patients. Their short\u2010term strategy involves: (1) Creating and running a preclinical platform to screen potential treatments using patient\u2010derived and animal models. (2) Clinical readiness, addressing challenges associated with low disease incidence and heterogeneity in clinical trial design, by developing multi\u2010domain endpoints, responder index, and biobanks\/biomarkers. (3) Target identification investigating SMAD4 pathogenic variants rewiring protein\u2013protein interactions in key signaling pathways. (4) Fostering partnerships with regulatory authorities, industries, and other patient research organizations. The MSF portfolio includes targeting fibrosis with immunotherapy using FAP\u2010CAR\u2010T cells, and a precision medicine approach aimed at restoring normal SMAD4 function through gene editing and small molecules. MSF aims to develop therapies that address both acute and chronic manifestations of this complex disease, improving the quality of life for affected individuals.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.c.32156","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T05:29:58Z","timestamp":1762234198000},"page":"290-305","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Navigating Drug Discovery for Myhre Syndrome: The Complexity of a Multisystemic Rare Disease"],"prefix":"10.1002","volume":"199","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1605-6722","authenticated-orcid":false,"given":"Armelle","family":"Pindon","sequence":"first","affiliation":[{"name":"Myhre Syndrome Foundation  Richardson Texas 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