A single versus multi-vector approach to treating post-traumatic osteoarthritis using scAAV2 IL-1ra or scAAV2 IL-1ra/IGF-I in an equine preclinical model

Abstract Interest in leveraging FDA approved "self-complementary" adeno-associated viral (scAAV) vectors for osteoarthritis treatment has been steadily rising. Due to the multi-faceted nature of osteoarthritis (an inflammatory/catabolic environment), we investigated the efficacy of a combined scAAV-based gene therapy approach to treating post-traumatic osteoarthritis (PTOA) in an equine preclinical model. Two approaches were established using scAAV2IL-1ra either alone or in combination with scAAV2IGF-I. All therapeutic proteins increased in the joints over the 4-month study period, (IL-1ra 218-300x & IGF-I 4x). Primary outcome measures, including clinical exams, MRI scoring, and gross and histological scoring of the joints revealed that scAAV2IL-1ra treatment alone consistently demonstrated the least PTOA progression. Surprisingly, the combination treated group (scAAV2IL-1ra + scAAV2IGF-I) demonstrated greater PTOA progression than the untreated controls. Exploratory data suggest this unexpected outcome may not be due to therapeutic transgenes but to dose-related, vector-induced immune responses. In summary, our observations strongly support optimizing scAAV for joint transduction & utilizing the highly translational equine model at reduced viral doses.