Mechanisms of carbon dot-guided rAAV gene vector formulation and release forimproved, safe rAAV-mediated therapeutic gene transfer in human cartilage lesions.

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Focal cartilage traumatic lesions are critical issues in orthopaedics since the adult articular cartilage does not completely heal on itself as a result of the lack of vascularization in this tissue. In light of the restricted ability of the cartilage for full self-healing, various options have been developed to improve cartilage repair, but none can fully heal cartilage lesions. Administration of the potent, clinically adapted recombinant adeno-associated virus (rAAV) vectors in focal cartilage defects is a strong approach to temporarily and spatially transfer chondroreparative genes in sites of injury for an extended expression of the gene products. Yet, the safe, clinical use of rAAV is still hindered by various obstacles in vivo, especially by the natural presence of neutralizing antibodies against the AAV capsid proteins in the human population. To address this issue, the goal of the present proposal is to test the hypothesis that therapeutic rAAV vectors coding for chondroreparative (proliferative, pro-anabolic) genes (the cartilage-specific sex-determining region Y-type high mobility box 9 - SOX9 - transcription factor and the transforming growth factor beta - TGF-ß) may be delivered via carbon dots (CDs) as protective, controlled delivery systems to safely, effectively, and durably enhance the processes and mechanisms relevant of cartilage repair in primary human bone marrow-derived mesenchymal stromal cells in a natural 3D environment in vitro, in a pre-translational model of human experimental osteochondral defect in situ, and in clinically relevant, translational focal cartilage defects in vivo relative to direct application of the vectors in their free form. This project may offer new, effective therapies to enhance cartilage repair in patients in a close future.