Chalberg, Thomas W

Interest in using gene therapy to treat osteoarthritis (OA) is growing and a number of clinical trials have been initiated. This commentary identifies three intersecting areas that need to be addressed for the field to move forward expeditiously. The first relates to lowering the cost of manufacturing clinical grade viral vectors, addressing various aspects of their deployment, and overcoming immune barriers to dosing and re-dosing. The second area requires an improved understanding of the pathophysiology of OA, including its stratification by endotype and phenotype. Coupled to the development of reliable biomarkers, this will enable the creation of personalized gene therapies, facilitate patient selection, and aid the identification of additional molecular targets. Moreover, progress in the early diagnosis of OA will enable administration of gene therapeutics at a stage when they are most likely to be successful. Finally, important issues with regard to financing and regulation are discussed. Top line data from two pivotal Phase III clinical trials are expected to be released this year. The findings from these trials will exercise considerable influence on the future development of the field.

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 × 10 11 viral genomes (vg)], mid (1 × 10 12 vg), or high (1 × 10 13 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.