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. doi: 10.1002/art.40668. Epub 2018 Sep 10.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Animals
  • Arthritis, Experimental / therapy*
  • Carpal Joints / diagnostic imaging
  • Carpal Joints / metabolism
  • Carpal Joints / pathology
  • Cartilage, Articular / diagnostic imaging
  • Cartilage, Articular / metabolism
  • Cartilage, Articular / pathology*
  • Disease Models, Animal
  • Forelimb
  • Genetic Therapy / methods*
  • Horses
  • Interleukin 1 Receptor Antagonist Protein / genetics*
  • Interleukin 1 Receptor Antagonist Protein / metabolism
  • Ligaments, Articular / surgery
  • Mice
  • Osteoarthritis / metabolism
  • Osteoarthritis / therapy*
  • Osteophyte / diagnostic imaging
  • Osteophyte / metabolism
  • Osteophyte / pathology*
  • Stifle / diagnostic imaging
  • Stifle / metabolism
  • Stifle / pathology*
  • Synovial Fluid / metabolism
  • Synovial Membrane / metabolism
  • Synovitis / diagnostic imaging
  • Synovitis / metabolism
  • Synovitis / pathology*
  • X-Ray Microtomography

Substances

  • Interleukin 1 Receptor Antagonist Protein

Grants and funding