Autologous transplantation of mitochondria/rAAV IGF-I platforms in human osteoarthritic articular chondrocytes as a novel therapeutic concept for human osteoarthritis

Despite various available treatments, highly prevalent osteoarthritis cannot be cured in patients. In light of evidence showing mitochondria dysfunction during the disease progression, our goal was to develop a novel therapeutic concept based on the transplantation of mitochondria as platforms to deliver recombinant adeno-associated viral (rAAV) gene vectors with a potency for osteoarthritis. For the first time to our best knowledge, we report the successful creation of a safe mitochondria/rAAV system effectively promoting the overexpression of a candidate insulin-like growth factor I (IGF-I) by administration to autologous human osteoarthritic articular chondrocytes versus control conditions (reporter mitochondria/rAAV lacZ system, rAAV-free system, absence of mitochondria transplantation) (up to 8.4-fold difference). The candidate mitochondria/rAAV IGF-I system significantly improved key activities in the transplanted cells (proliferation/survival, extracellular matrix production, mitochondria functions) relative to the control conditions (up to 9.5-fold difference), including when provided in a PF127 hydrogel for reinforced delivery (up to 5.9-fold difference). Such effects were accompanied with increased levels of cartilage-specific SOX9 and Mfn-1 (mitochondria fusion) and with decreased levels of Drp-1 (mitochondria fission) and proinflammatory TNF-α (up to 4.5-fold difference). This study shows the potential of combining the use of mitochondria with rAAV as a promising approach for human OA.