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A notable milestone in this journey was the first\u2010in\u2010human transfer of an exogenous gene to a joint, accomplished by the ex vivo delivery of cDNA encoding the interleukin\u20101 receptor antagonist (IL\u20101Ra) to joints of patients with rheumatoid arthritis. Responding to lessons learned from this study and the prevailing clinical landscape we next developed an in vivo gene delivery system based on adeno\u2010associated virus (AAV) with osteoarthritis (OA) as the target disease. The safety and efficacy of this vector, sc\u2010rAAV2.5IL\u20101Ra, was demonstrated in the joints of rats and horses leading to a successful IND application to the FDA. In this clinical trial (ClinicalTrials. gov Identifier: NCT02790723) sc\u2010rAAV2.5IL\u20101Ra was injected at escalating doses into the knee joints of nine patients with OA who were followed for 1 year. This trial met its primary outcome measure, safety, and demonstrated that sustained expression of transgenic IL\u20101Ra was possible after a single injection of the vector. Patient\u2010reported outcomes improved, but without a control group it is not possible to determine the influence of a placebo effect. This and other unresolved matters are addressed in a recently\u2010completed Phase Ib trial (ClinicalTrials. gov Identifier: NCT05835895). Beyond OA, sc\u2010rAAV2.5IL\u20101Ra has potential therapeutic value in a variety of degenerative, inflammatory, fibrotic and autoimmune conditions. More generally, gene therapy holds much promise in the field of regenerative medicine, including regenerative orthopaedics.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    (ClinicalTrials. gov Identifier: NCT02790723, NCT05835895).\n                  <\/jats:p>","DOI":"10.1002\/jor.70141","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T06:17:59Z","timestamp":1769667479000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Osteoarthritis Gene Therapy: A 30\u2010Year Journey From Concept to Clinical Trials"],"prefix":"10.1002","volume":"44","author":[{"given":"Christopher H.","family":"Evans","sequence":"first","affiliation":[{"name":"Departments of Physical Medicine &amp; Rehabilitation, Orthopaedic Surgery, and Molecular Medicine Mayo Clinic Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Ghivizzani","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Rehabilitation University of Florida College of Medicine Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D.","family":"Robbins","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Biophysics University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apmr.2020.04.001"},{"key":"e_1_2_12_3_1","volume-title":"Evidence\u2010Based Clinical Practice Guideline","author":"American Academy of Orthopaedic Surgeons","year":"2021"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.2165\/00063030-200519060-00003"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l6923"},{"key":"e_1_2_12_6_1","first-page":"1386","article-title":"Prevalence of Total Hip and Knee Replacement in the United States","volume":"97","author":"Maradit Kremers H.","year":"2015","journal-title":"Journal of Bone and Joint Surgery\u2010American Volume"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2013.159"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1089\/dna.1992.11.227"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.181"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.22.10764"},{"key":"e_1_2_12_11_1","first-page":"515","article-title":"Neutralization of Interleukin\u20101 Beta Activity In Vivo With a Monoclonal Antibody Alleviates Collagen\u2010Induced Arthritis in DBA\/1 Mice and Prevents the Associated Acute\u2010Phase Response","volume":"11","author":"Geiger T.","year":"1993","journal-title":"Clinical and Experimental Rheumatology"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/343341a0"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/343336a0"},{"key":"e_1_2_12_14_1","first-page":"64","article-title":"Suppression of Intra\u2010Articular Responses to Interleukin\u20101 by Transfer of the Interleukin\u20101 Receptor Antagonist Gene to Synovium","volume":"1","author":"Hung G. 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