Disease‐Modifying Osteoarthritis Treatment With Interleukin‐1 Receptor Antagonist Gene Therapy in Small and Large Animal Models

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2018-11, Vol.70 (11), p.1757-1768
• Main Authors: Nixon, Alan J., Grol, Matthew W., Lang, Hayley M., Ruan, Merry Z. C., Stone, Adrianne, Begum, Laila, Chen, Yuqing, Dawson, Brian, Gannon, Francis, Plutizki, Stanislav, Lee, Brendan H. L., Guse, Kilian
• Format: Article
• Language: English
• Subjects: Adenoviridae; Animal models; Animals; Arthritis; Arthritis, Experimental - therapy; Biocompatibility; Carpal Joints - diagnostic imaging; Carpal Joints - metabolism; Carpal Joints - pathology; Cartilage; Cartilage diseases; Cartilage, Articular - diagnostic imaging; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Computed tomography; Cytokines; Disease Models, Animal; Effectiveness; Forelimb; Gene expression; Gene therapy; Genetic Therapy - methods; Horses; Interleukin 1 Receptor Antagonist Protein - genetics; Interleukin 1 Receptor Antagonist Protein - metabolism; Interleukins; Ligaments, Articular - surgery; Mathematical models; Medical treatment; Mice; Organic chemistry; Osteoarthritis; Osteoarthritis - metabolism; Osteoarthritis - therapy; Osteophyte - diagnostic imaging; Osteophyte - metabolism; Osteophyte - pathology; Osteophytes; Pain perception; Parameter modification; Proteins; Stifle - diagnostic imaging; Stifle - metabolism; Stifle - pathology; Synovial fluid; Synovial Fluid - metabolism; Synovial membrane; Synovial Membrane - metabolism; Synovitis; Synovitis - diagnostic imaging; Synovitis - metabolism; Synovitis - pathology; X-Ray Microtomography
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.40668

Objective Gene therapy holds great promise for the treatment of osteoarthritis (OA) because a single intraarticular 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 intraarticular gene therapy approach for long‐term expression of interleukin‐1 receptor antagonist (IL‐1Ra) as sustained symptomatic and disease‐modifying therapy for OA. Methods In mouse models of OA, efficacy of HDAd–IL‐1Ra was evaluated by histologic analysis, micro–computed tomography (micro‐CT), and hot plate analysis. In a horse OA model, 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–interleukin‐1 receptor antagonist 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. Furthermore, this study establishes HDAd as a vector for joint gene therapy.