{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T13:15:39Z","timestamp":1793193339803,"version":"4.5.0"},"reference-count":36,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T00:00:00Z","timestamp":1694131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["P01AI100263"],"award-info":[{"award-number":["P01AI100263"]}]},{"name":"NIH","award":["R01NS076991"],"award-info":[{"award-number":["R01NS076991"]}]},{"name":"NIH","award":["P01HD080642"],"award-info":[{"award-number":["P01HD080642"]}]},{"name":"NIH","award":["R01AI12135"],"award-info":[{"award-number":["R01AI12135"]}]},{"name":"NIH","award":["R21AR077557"],"award-info":[{"award-number":["R21AR077557"]}]},{"name":"NIH","award":["R01AR078230"],"award-info":[{"award-number":["R01AR078230"]}]},{"name":"NIH\/NIAMS","award":["P01AI100263"],"award-info":[{"award-number":["P01AI100263"]}]},{"name":"NIH\/NIAMS","award":["R01NS076991"],"award-info":[{"award-number":["R01NS076991"]}]},{"name":"NIH\/NIAMS","award":["P01HD080642"],"award-info":[{"award-number":["P01HD080642"]}]},{"name":"NIH\/NIAMS","award":["R01AI12135"],"award-info":[{"award-number":["R01AI12135"]}]},{"name":"NIH\/NIAMS","award":["R21AR077557"],"award-info":[{"award-number":["R21AR077557"]}]},{"name":"NIH\/NIAMS","award":["R01AR078230"],"award-info":[{"award-number":["R01AR078230"]}]},{"name":"International FOP Association, and AAVAA Therapeutics","award":["P01AI100263"],"award-info":[{"award-number":["P01AI100263"]}]},{"name":"International FOP Association, and AAVAA Therapeutics","award":["R01NS076991"],"award-info":[{"award-number":["R01NS076991"]}]},{"name":"International FOP Association, and AAVAA Therapeutics","award":["P01HD080642"],"award-info":[{"award-number":["P01HD080642"]}]},{"name":"International FOP Association, and AAVAA Therapeutics","award":["R01AI12135"],"award-info":[{"award-number":["R01AI12135"]}]},{"name":"International FOP Association, and AAVAA Therapeutics","award":["R21AR077557"],"award-info":[{"award-number":["R21AR077557"]}]},{"name":"International FOP Association, and AAVAA Therapeutics","award":["R01AR078230"],"award-info":[{"award-number":["R01AR078230"]}]},{"name":"Isaac &amp; Rose Nassau Professorship of Orthopedic Molecular Medicine","award":["P01AI100263"],"award-info":[{"award-number":["P01AI100263"]}]},{"name":"Isaac &amp; Rose Nassau Professorship of Orthopedic Molecular Medicine","award":["R01NS076991"],"award-info":[{"award-number":["R01NS076991"]}]},{"name":"Isaac &amp; Rose Nassau Professorship of Orthopedic Molecular Medicine","award":["P01HD080642"],"award-info":[{"award-number":["P01HD080642"]}]},{"name":"Isaac &amp; Rose Nassau Professorship of Orthopedic Molecular Medicine","award":["R01AI12135"],"award-info":[{"award-number":["R01AI12135"]}]},{"name":"Isaac &amp; Rose Nassau Professorship of Orthopedic Molecular Medicine","award":["R21AR077557"],"award-info":[{"award-number":["R21AR077557"]}]},{"name":"Isaac &amp; Rose Nassau Professorship of Orthopedic Molecular Medicine","award":["R01AR078230"],"award-info":[{"award-number":["R01AR078230"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal sites. Here, we developed adeno-associated virus (AAV)-based gene therapy that suppresses trauma-induced HO in FOP mice harboring a heterozygous allele of human ACVR1R206H (Acvr1R206H\/+) while limiting the expression in non-skeletal organs such as the brain, heart, lung, liver, and kidney. AAV gene therapy carrying the combination of codon-optimized human ACVR1 (ACVR1opt) and artificial miRNAs targeting Activin A and its receptor ACVR1R206H ablated the aberrant activation of BMP-Smad1\/5 signaling and the osteogenic differentiation of Acvr1R206H\/+ skeletal progenitors. The local delivery of AAV gene therapy to HO-causing cells in the skeletal muscle resulted in a significant decrease in endochondral bone formation in Acvr1R206H\/+ mice. These mice showed little to no expression in a major AAV-targeted organ, the liver, due to liver-abundant miR-122-mediated repression. Thus, AAV gene therapy is a promising therapeutic strategy to explore in suppressing HO in FOP.<\/jats:p>","DOI":"10.3390\/biom13091364","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T07:52:11Z","timestamp":1694159531000},"page":"1364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["AAV-Mediated Targeting of the Activin A-ACVR1R206H Signaling in Fibrodysplasia Ossificans Progressiva"],"prefix":"10.3390","volume":"13","author":[{"given":"Yeon-Suk","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chujiao","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Ma","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"},{"name":"Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"},{"name":"Viral Vector Core, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xie","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"},{"name":"Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"},{"name":"Viral Vector Core, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick S.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Medicine, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"The Center for Research in FOP and Related Disorders, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangping","family":"Gao","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"},{"name":"Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"},{"name":"Viral Vector Core, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"},{"name":"Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4947-3293","authenticated-orcid":false,"given":"Jae-Hyuck","family":"Shim","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"},{"name":"Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"},{"name":"Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1186\/s13023-021-01983-2","article-title":"Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: Estimate from three treatment centers and a patient organization","volume":"16","author":"Pignolo","year":"2021","journal-title":"Orphanet J. 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