Gene Therapy for OA

Background & objective: One of the major challenges in the treatment of chronic joint diseases, such as osteoarthritis (OA), is the need to provide sustained bioavailability of a therapeutic agent within the joint. Systemically administered drugs cannot sufficiently reach the synovial space, and intra-articularly injected agents are cleared from the joint fluid rapidly by the lymphatic system, which severely compromises their bioavailability. Gene therapy holds great promise for the treatment of OA because a single intra-articular injection can lead to long-term expression of therapeutic proteins within the joint.

This study was undertaken to investigate the use of a helper-dependent adenovirus (HDAd)–mediated intra-articular gene therapy approach for long-term expression of interleukin 1 receptor antagonist (IL-1Ra) as a sustained symptomatic and disease-modifying therapy for OA.

Methods: In mouse models of OA, the efficacy of HDAd–IL-1Ra was evaluated by histologic analysis, micro–computed tomography (micro-CT) and hot plate analysis. In a horse OA model, the safety and efficacy of HDAd–IL-1Ra were evaluated by blood chemistry, analyses of synovial fluid, synovial membrane and cartilage, and gross pathology and lameness assessments.

Results: In skeletally immature mice, HDAd–IL-1Ra prevented development of cartilage damage, osteophytes and synovitis. In skeletally immature and mature mice, treatment with HDAd–IL-1Ra post–OA induction resulted in improved—albeit not significantly—cartilage status assessed histologically and significantly increased cartilage volume, cartilage surface and bone surface covered by cartilage as assessed by micro-CT. Fewer osteophytes were observed in HDAd–IL-1Ra–treated skeletally immature mice. Synovitis was not affected in skeletally immature or mature mice. HDAd–IL-1Ra protected against disease-induced thermal hyperalgesia in skeletally mature mice.

In the horse OA model, HDAd–IL-1Ra therapy significantly improved lameness parameters, indicating efficient symptomatic treatment. Moreover, macroscopically and histologically assessed cartilage and synovial membrane parameters were significantly improved, suggesting disease-modifying efficacy.

Conclusion: These data from OA models in small and large animals demonstrated safe symptomatic and disease-modifying treatment with an HDAd-expressing IL-1Ra. Further, this study establishes HDAd as a vector for joint gene therapy. 

Excerpted and adapted from:
Nixon AJ, Grol MW, Lang HM, et al. Disease-modifying osteoarthritis treatment with interleukin-1 receptor antagonist gene therapy in small and large animal models. Arthritis Rheumatol. 2018 Nov;70(11):1757–1768