{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T16:06:56Z","timestamp":1793203616542,"version":"4.5.0"},"reference-count":38,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"801","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/www.science.org\/content\/page\/science-licenses-journal-article-reuse"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,6,4]]},"abstract":"<jats:p>\n                    Osteoarthritis (OA) is a major global health problem with no disease-modifying therapies. Interleukin-1 (IL-1) is a critical cytokine associated with the pathophysiology of OA and can be inhibited by IL-1 receptor antagonist (IL-1Ra). Here, we tested the delivery of a gene therapeutic encoding the human IL-1Ra to the knee in a phase 1, open-label clinical trial that enrolled nine patients with radiographic knee OA. The IL-1Ra gene was delivered by a self-complementary (sc)\u2013recombinant adeno-associated virus (rAAV) serotype 2.5 (sc-rAAV2.5IL-1Ra) by intra-articular injection into an index knee at one of three doses: low [1\u00a0\u00d7\u00a010\n                    <jats:sup>11<\/jats:sup>\n                    viral genomes (vg)], mid (1\u00a0\u00d7\u00a010\n                    <jats:sup>12<\/jats:sup>\n                    vg), or high (1\u00a0\u00d7\u00a010\n                    <jats:sup>13<\/jats:sup>\n                    vg). The primary outcome was safety. There were no serious adverse events (AEs) related to sc-rAAV2.5IL-1Ra. Two AEs occurred that were possibly related to the vector. Both were effusions with increased pain and resolved with conservative treatment. sc-rAAV2.5IL-1Ra did not cause changes in vital signs, physical findings, or clinical laboratory measures. Less than 1% of the injected dose of sc-rAAV2.5IL-1Ra vg was detected in circulation after 1 day and was cleared within a week. Titers of neutralizing antibodies to AAV2.5 rose in serum and synovial fluid. In all cases, IL-1Ra concentration increased in the synovial fluid, and IL-1Ra concentrations remained elevated after 1 year. Baseline pain and function scores improved during the study. Therefore, we found that intra-articular gene therapy with sc-rAAV2.5IL-1Ra was safe. The sustained increase in local IL-1Ra in human knee joints supports the further clinical examination of this therapy to provide therapeutic benefit in OA.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adu9804","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T13:58:46Z","timestamp":1749045526000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":38,"title":["A phase 1 clinical trial shows safe, sustained, AAV-mediated expression of IL-1Ra in the human osteoarthritic knee joint"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2196-8729","authenticated-orcid":true,"given":"Rodolfo E.","family":"De la Vega","sequence":"first","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Musculoskeletal Gene Therapy Laboratory, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob L.","family":"Sellon","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Wisniewski","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3127-2108","authenticated-orcid":true,"given":"Mary L.","family":"Jurisson","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Frick","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyson L.","family":"Scrabeck","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie B.","family":"Block","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candee J.","family":"Mills","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary W.","family":"Pohlkamp","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Coenen","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Musculoskeletal Gene Therapy Laboratory, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5202-9899","authenticated-orcid":true,"given":"Gresin P.","family":"Hawse","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Musculoskeletal Gene Therapy Laboratory, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4561-8213","authenticated-orcid":true,"given":"Temilola Y.","family":"Abdul","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Musculoskeletal Gene Therapy Laboratory, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Department of Clinical Pharmacology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3478-5665","authenticated-orcid":true,"given":"Philip","family":"Conaghan","sequence":"additional","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds LS7 4SA, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annahita","family":"Keravala","sequence":"additional","affiliation":[{"name":"Genascence Corp., Palo Alto, CA 94306, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8653-6735","authenticated-orcid":true,"given":"Thomas W.","family":"Chalberg","sequence":"additional","affiliation":[{"name":"Genascence Corp., Palo Alto, CA 94306, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1068-7099","authenticated-orcid":true,"given":"Paul D.","family":"Robbins","sequence":"additional","affiliation":[{"name":"Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5154-7581","authenticated-orcid":true,"given":"Steven C.","family":"Ghivizzani","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL 32610, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5532-2347","authenticated-orcid":true,"given":"Christopher H.","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Musculoskeletal Gene Therapy Laboratory, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2022.101810"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2013.159"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02632-w"},{"key":"e_1_3_2_5_2","first-page":"CD005328","article-title":"Intra-articular corticosteroid for knee osteoarthritis","volume":"2015","author":"J\u00fcni P.","year":"2015","unstructured":"P. J\u00fcni, R. Hari, A. W. S. Rutjes, R. Fischer, M. G. Silletta, S. Reichenbach, B. R. da Costa, Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst. Rev. 2015, CD005328 (2015).","journal-title":"Cochrane Database Syst. Rev."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.34453"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24096"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1089\/dna.1992.11.227"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.181"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000918"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502854102"},{"key":"e_1_3_2_12_2","first-page":"983","article-title":"Empirical advantages of adeno associated viral vectors in vivo gene therapy for arthritis","volume":"27","author":"Goater J.","year":"2000","unstructured":"J. Goater, R. M\u00fcller, G. Kollias, G. S. Firestein, I. Sanz, R. J. O'Keefe, E. M. Schwarz, Empirical advantages of adeno associated viral vectors in vivo gene therapy for arthritis. J. Rheumatol. 27, 983\u2013989 (2000).","journal-title":"J. Rheumatol."},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.5435\/JAAOS-D-24-00831"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.089375"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.090817"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar2411"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0801066"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2021.09.013"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1089\/humc.2017.249"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-018-0009-5"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1089\/humc.2017.142"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1089\/humc.2017.143"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/mtm.2015.52"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132706"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2024.07.016"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.87.3.8351"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780360607"},{"key":"e_1_3_2_29_2","first-page":"1650","article-title":"A high interleukin 1 receptor antagonist\/IL-1\u03b2 ratio occurs naturally in knee osteoarthritis","volume":"35","author":"Richette P.","year":"2008","unstructured":"P. Richette, M. Fran\u00e7ois, E. Vicaut, C. Fitting, T. Bardin, M. Corvol, J.-F. Savouret, F. Rannou, A high interleukin 1 receptor antagonist\/IL-1\u03b2 ratio occurs naturally in knee osteoarthritis. J. Rheumatol. 35, 1650\u20131654 (2008).","journal-title":"J. Rheumatol."},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.51.6.731"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/jor.22334"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-014-0441-0"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41434-022-00326-5"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.666666"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.RVW.18.00150"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.294"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216055"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2010.12.003"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.113043"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adu9804","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adu9804","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T13:58:52Z","timestamp":1749045532000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adu9804"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,4]]},"references-count":38,"journal-issue":{"issue":"801","published-print":{"date-parts":[[2025,6,4]]}},"alternative-id":["10.1126\/scitranslmed.adu9804"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adu9804","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,4]]},"assertion":[{"value":"2024-12-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-03","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadu9804"}}