Mechanisms of pNaSS-grafted poly(epsilon-caprolactone) scaffold-guided rAAV-mediated gene transfer for enhanced, safe human anterior cruciate ligament repair

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Injuries of the knee anterior cruciate ligament (ACL) are prevalent, critical issues and a socioeconomical burden in orthopaedics, potentially leading to osteoarthritis, since the ACL has a limited intrinsic ability for self healing. As none of the current clinical (conservative, surgical) interventions support the durable, full repair of ACL lesions, innovative options based on gene therapy may provide strong tools to enhance the processes of ACL repair. Administration of the potent, clinically adapted recombinant adeno-associated virus (rAAV) vectors in ACL lesions is a potent approach to temporarily and spatially transfer reparative genes in sites of injury for a prolonged expression of the gene products. Still, the safe, clinical use of rAAV remains impeded by diverse obstacles in vivo, especially by the presence of natural neutralizing antibodies against the AAV capsid proteins in humans. To address this challenging issue, the goal of the present proposal is to test the hypothesis that therapeutic rAAV vectors coding for reparative (proliferative, pro-anabolic) genes (the basic fibroblast growth factor - FGF-2 - and the transforming growth factor beta - TGF-ß) may be delivered via functionalized poly(sodium styrene sulfonate)-grafted poly(epsilon-caprolactone) (pNaSS-grafted PCL) films as protective, controlled delivery platforms to safely, effectively, and durably enhance the processes and mechanisms relevant of ACL repair in a pre-translational model of human experimental ACL lesions ex vivo, including in conditions of experimental humoral neutralization, and in clinically relevant, translational experimental ACL lesions in vivo relative to direct application of the vectors in their film-free form. This project may offer new, effective therapies to enhance ACL repair in patients in a close future.