{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T04:55:32Z","timestamp":1791089732115,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2018,9,10]],"date-time":"2018-09-10T00:00:00Z","timestamp":1536537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Gene therapy holds great promise for the treatment of osteoarthritis (<jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content>) because a single intraarticular injection can lead to long\u2010term expression of therapeutic proteins within the joint. This study was undertaken to investigate the use of a helper\u2010dependent adenovirus (<jats:styled-content style=\"fixed-case\">HDA<\/jats:styled-content>d)\u2013mediated intraarticular gene therapy approach for long\u2010term expression of interleukin\u20101 receptor antagonist (<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101Ra) as sustained symptomatic and disease\u2010modifying therapy for <jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In mouse models of <jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content>, efficacy of <jats:styled-content style=\"fixed-case\">HDA<\/jats:styled-content>d\u2013<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101Ra was evaluated by histologic analysis, micro\u2013computed tomography (micro\u2010<jats:styled-content style=\"fixed-case\">CT<\/jats:styled-content>), and hot plate analysis. In a horse <jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content> model, safety and efficacy of <jats:styled-content style=\"fixed-case\">HDA<\/jats:styled-content>d\u2013<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101Ra were evaluated by blood chemistry, analyses of synovial fluid, synovial membrane, and cartilage, and gross pathology and lameness assessments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In skeletally immature mice, <jats:styled-content style=\"fixed-case\">HDA<\/jats:styled-content>d\u2013<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101Ra prevented development of cartilage damage, osteophytes, and synovitis. In skeletally immature and mature mice, treatment with <jats:styled-content style=\"fixed-case\">HDA<\/jats:styled-content>d\u2013<jats:styled-content style=\"fixed-case\">interleukin<\/jats:styled-content>\u20101 receptor antagonist post\u2013<jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content> induction resulted in improved\u2014albeit not significantly\u2014cartilage status assessed histologically and significantly increased cartilage volume, cartilage surface, and bone surface covered by cartilage as assessed by micro\u2010<jats:styled-content style=\"fixed-case\">CT<\/jats:styled-content>. Fewer osteophytes were observed in <jats:styled-content style=\"fixed-case\">HDA<\/jats:styled-content>d\u2013<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101Ra\u2013treated skeletally immature mice. Synovitis was not affected in skeletally immature or mature mice. <jats:styled-content style=\"fixed-case\">HDA<\/jats:styled-content>d\u2013<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101Ra protected against disease\u2010induced thermal hyperalgesia in skeletally mature mice. In the horse <jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content> model, <jats:styled-content style=\"fixed-case\">HDA<\/jats:styled-content>d\u2013<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101Ra therapy significantly improved lameness parameters, indicating efficient symptomatic treatment. Moreover, macroscopically and histologically assessed cartilage and synovial membrane parameters were significantly improved, suggesting disease\u2010modifying efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data from <jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content> models in small and large animals demonstrated safe symptomatic and disease\u2010modifying treatment with an <jats:styled-content style=\"fixed-case\">HDA<\/jats:styled-content>d\u2010expressing <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101Ra. Furthermore, this study establishes <jats:styled-content style=\"fixed-case\">HDA<\/jats:styled-content>d as a vector for joint gene therapy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40668","type":"journal-article","created":{"date-parts":[[2018,7,25]],"date-time":"2018-07-25T13:01:29Z","timestamp":1532523689000},"page":"1757-1768","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Disease\u2010Modifying Osteoarthritis Treatment With Interleukin\u20101 Receptor Antagonist Gene Therapy in Small and Large Animal Models"],"prefix":"10.1002","volume":"70","author":[{"given":"Alan J.","family":"Nixon","sequence":"first","affiliation":[{"name":"Cornell University Ithaca New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W.","family":"Grol","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayley M.","family":"Lang","sequence":"additional","affiliation":[{"name":"Cornell University Ithaca New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merry Z. 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