Mechanisms of alginate/rAAV gene vector encapsulation and release for enhanced, saferAAV-mediated therapeutic gene transfer in human meniscal lesions

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Lesions to the meniscus, a vital tissue in the knee joint, are highly prevalent, unsolved problems in sports medicine and may predispose the adjacent articular cartilage to osteoarthritis if left untreated. In light of the restricted ability of the meniscus for complete self-healing especially in its avascular zone, various options have been developed to improve meniscal repair, but none can fully heal meniscal lesions, being also limited by the availability, rejection, and/or failure of allograft/substitutes in the clinics. Administration of the potent, clinically adapted recombinant adeno-associated virus (rAAV) vectors in meniscal lesions is a strong approach to temporarily and spatially transfer meniscal reparative 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 meniscal reparative (proliferative, pro-anabolic) genes (basic fibroblast growth factor - FGF-2, transforming growth factor beta - TGF- ß) may be delivered via hydrogels based on clinically approved alginate as protective, controlled delivery systems to safely, effectively, and durably enhance the processes and mechanisms relevant of meniscal repair in primary human meniscal fibrochondrocytes in vitro, in a pre-translational model of human experimental meniscal lesion in situ, and in clinically relevant, translational meniscal lesions in vivo relative to direct application of the vectors in their free form. This project may offer new, effective therapies to enhance meniscal repair in patients in a close future.