A pilot study to determine the optimal dose of scAAVIL-1ra in a large animal model of post-traumatic osteoarthritis

Abstract

Gene therapy approaches using adeno-associated viral vectors have been successfully tested in the equine post-traumatic osteoarthritis (PTOA) model. Owing to differences in the levels of transgene expression and adverse tissue reactions observed in published studies, we sought to identify a safe therapeutic dose of scAAVIL-1ra in an inflamed and injured joint that would result in improved functional outcomes without any adverse events. scAAVIL-1ra was delivered intra-articularly over a 100-fold range, and horses were evaluated throughout and at the end of the 10-week study. A dose-related increase in IL-1ra levels with a decrease in PGE2 levels was observed, with the peak IL-1ra concentration being observed 7 days post-treatment in all groups. Perivascular infiltration with mononuclear cells was observed within the synovial membrane of the joint treated with the highest viral dose of 5 × 1012 vg, but this was absent in the lower-dosed joints. The second-highest dose of scAAVeqIL-1ra 5 × 1011 vg demonstrated elevated IL-1ra levels without any cellular response in the synovium. Taken together, the data suggest that the 10-fold lower dose of 5 × 1011vg scAAVIL-1ra would be a safe therapeutic dose in an equine model of PTOA.

A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine

“…IL-1 is a prominent player in OA pathogenesis, particularly in post-traumatic OA (PTOA), and increased levels in serum and synovial fluid correlate with OA incidence and severity (58, 72, 73). Viral delivery of IL-1Ra has improved outcomes of PTOA in large animal models, but safety concerns for delivery to the joint include increased infections due to prolonged IL-1 suppression and perivascular cuffing secondary to viral gene therapy (57, 74, 75). Here, IL-1Ra-expressing CII-synNotch cells modulated the IL-1α-induced inflammatory response of ATDC5 chondrocytes, as measured by NF-κB transcriptional activity and qRT-PCR profiling of several inflammation-responsive genes.…”

“…With the goal of generating a synthetically regulated MSC line capable of mitigating an inflammatory environment in response to cartilage damage, CII-synNotch MSCs were engineered with inducible human IL-1 receptor antagonist (IL-1Ra). IL-1Ra is an established anti-inflammatory biologic that is clinically used in the treatment of rheumatoid arthritis (56), and has demonstrated preclinical benefits in the treatment of OA (25,43,(57)(58)(59)(60). Thus, we engineered a synNotch-inducible IL-1Ra MSC line.…”

A Translational Model for Repeated Episodes of Joint Inflammation: Welfare, Clinical and Synovial Fluid Biomarker Assessment

“…The currently commonly available therapies are symptomatic, show limited effectiveness, and come with adverse effects [4,5]. Many novel therapeutics, ranging from oral neutraceuticals [6,7] to gene therapies [8], have been investigated in the drive to develop better therapies for controlling joint inflammation and therefore preventing OA development and progression in both horses and humans.…”