{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:43:57Z","timestamp":1787028237073,"version":"build-2736575974"},"reference-count":154,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:00:00Z","timestamp":1701302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund, the HM Toupin Neurological Science Research Fund, Canadian Institutes of Health Research","award":["CIHR"],"award-info":[{"award-number":["CIHR"]}]},{"name":"Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund, the HM Toupin Neurological Science Research Fund, Canadian Institutes of Health Research","award":["PS183733"],"award-info":[{"award-number":["PS183733"]}]},{"name":"Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund, the HM Toupin Neurological Science Research Fund, Canadian Institutes of Health Research","award":["PS183719"],"award-info":[{"award-number":["PS183719"]}]},{"name":"Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund, the HM Toupin Neurological Science Research Fund, Canadian Institutes of Health Research","award":["PS180495"],"award-info":[{"award-number":["PS180495"]}]},{"name":"Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund, the HM Toupin Neurological Science Research Fund, Canadian Institutes of Health Research","award":["PS175261"],"award-info":[{"award-number":["PS175261"]}]},{"name":"Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund, the HM Toupin Neurological Science Research Fund, Canadian Institutes of Health Research","award":["PS169193"],"award-info":[{"award-number":["PS169193"]}]},{"name":"Alberta Innovates: Health Solutions (AIHS), Jesse\u2019s Journey, and the Women and Children\u2019s Health Research Institute (WCHRI)","award":["CIHR"],"award-info":[{"award-number":["CIHR"]}]},{"name":"Alberta Innovates: Health Solutions (AIHS), Jesse\u2019s Journey, and the Women and Children\u2019s Health Research Institute (WCHRI)","award":["PS183733"],"award-info":[{"award-number":["PS183733"]}]},{"name":"Alberta Innovates: Health Solutions (AIHS), Jesse\u2019s Journey, and the Women and Children\u2019s Health Research Institute (WCHRI)","award":["PS183719"],"award-info":[{"award-number":["PS183719"]}]},{"name":"Alberta Innovates: Health Solutions (AIHS), Jesse\u2019s Journey, and the Women and Children\u2019s Health Research Institute (WCHRI)","award":["PS180495"],"award-info":[{"award-number":["PS180495"]}]},{"name":"Alberta Innovates: Health Solutions (AIHS), Jesse\u2019s Journey, and the Women and Children\u2019s Health Research Institute (WCHRI)","award":["PS175261"],"award-info":[{"award-number":["PS175261"]}]},{"name":"Alberta Innovates: Health Solutions (AIHS), Jesse\u2019s Journey, and the Women and Children\u2019s Health Research Institute (WCHRI)","award":["PS169193"],"award-info":[{"award-number":["PS169193"]}]},{"name":"Maternal and Child Health (MatCH) Program","award":["CIHR"],"award-info":[{"award-number":["CIHR"]}]},{"name":"Maternal and Child Health (MatCH) Program","award":["PS183733"],"award-info":[{"award-number":["PS183733"]}]},{"name":"Maternal and Child Health (MatCH) Program","award":["PS183719"],"award-info":[{"award-number":["PS183719"]}]},{"name":"Maternal and Child Health (MatCH) Program","award":["PS180495"],"award-info":[{"award-number":["PS180495"]}]},{"name":"Maternal and Child Health (MatCH) Program","award":["PS175261"],"award-info":[{"award-number":["PS175261"]}]},{"name":"Maternal and Child Health (MatCH) Program","award":["PS169193"],"award-info":[{"award-number":["PS169193"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Fibrodysplasia ossificans progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective tissues undergo pathological transformation into bone structures. This incapacitating process severely limits patient mobility and poses formidable challenges for therapeutic intervention. Predominantly caused by missense mutations in the ACVR1 gene, this disorder has hitherto defied comprehensive mechanistic understanding and effective treatment paradigms. This write-up offers a comprehensive overview of the contemporary understanding of FOP\u2019s complex pathobiology, underscored by advances in molecular genetics and proteomic studies. We delve into targeted therapy, spanning genetic therapeutics, enzymatic and transcriptional modulation, stem cell therapies, and innovative immunotherapies. We also highlight the intricate complexities surrounding clinical trial design for ultra-rare disorders like FOP, addressing fundamental statistical limitations, ethical conundrums, and methodological advancements essential for the success of interventional studies. We advocate for the adoption of a multi-disciplinary approach that converges bench-to-bedside research, clinical expertise, and ethical considerations to tackle the challenges of ultra-rare diseases like FOP and comparable ultra-rare diseases. In essence, this manuscript serves a dual purpose: as a definitive scientific resource for ongoing and future FOP research and a call to action for innovative solutions to address methodological and ethical challenges that impede progress in the broader field of medical research into ultra-rare conditions.<\/jats:p>","DOI":"10.3390\/genes14122162","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:34:10Z","timestamp":1701304450000},"page":"2162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Navigating the Complex Landscape of Fibrodysplasia Ossificans Progressiva: From Current Paradigms to Therapeutic Frontiers"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3688-5923","authenticated-orcid":false,"given":"Saeed","family":"Anwar","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6672-6742","authenticated-orcid":false,"given":"Toshifumi","family":"Yokota","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1385\/BMM:3:3-4:183","article-title":"The Phenotype of Fibrodysplasia Ossificans Progressiva","volume":"3","author":"Kaplan","year":"2005","journal-title":"Clin. 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