TY - JOUR
T1 - A phase 1 clinical trial shows safe, sustained, AAV-mediated expression of IL-1Ra in the human osteoarthritic knee joint
AU - De la Vega, Rodolfo E.
AU - Sellon, Jacob L.
AU - Smith, Jay
AU - Wisniewski, Stephen J.
AU - Jurisson, Mary L.
AU - Frick, Matthew A.
AU - Scrabeck, Tyson L.
AU - Block, Julie B.
AU - Mills, Candee J.
AU - Pohlkamp, Zachary W.
AU - Coenen, Michael J.
AU - Hawse, Gresin P.
AU - Abdul, Temilola Y.
AU - Conaghan, Philip
AU - Keravala, Annahita
AU - Chalberg, Thomas W.
AU - Robbins, Paul D.
AU - Ghivizzani, Steven C.
AU - Evans, Christopher H.
N1 - Publisher Copyright:
Copyright © 2025 The Authors, some rights reserved;
PY - 2025/6/4
Y1 - 2025/6/4
N2 - 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)–recombinant 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 × 1011 viral genomes (vg)], mid (1 × 1012 vg), or high (1 × 1013 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.
AB - 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)–recombinant 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 × 1011 viral genomes (vg)], mid (1 × 1012 vg), or high (1 × 1013 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=105007418705&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adu9804
DO - 10.1126/scitranslmed.adu9804
M3 - Article
C2 - 40465688
AN - SCOPUS:105007418705
SN - 1946-6234
VL - 17
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 801
M1 - eadu9804
ER -