Mechanisms of pNaSS-grafted poly(epsilon)-caprolactone scaffolds for enhanced rAAV-mediated gene transfer in human bone marrow-derived mesenchymal stem cells

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Focal articular cartilage lesions remain major, unresolved problems in orthopaedic surgery as none of the therapeutic options available thus far can fully restore the structural and functional (mechanical) integrity of the native cartilage. Administration of the potent, clinically adapted recombinant adeno-associated virus (rAAV) vectors in sites of cartilage injury is a strong approach to target the resident, chondroregenerative mesenchymal stem cells (MSCs) within their natural, concentrated microenvironment by delivery of highly chondrogenic genes such as the transforming growth factor beta (TGF-ß) and cartilage-specific sex-determining region Y-type high mobility group box 9 (SOX9) transcription factor. However, while rAAV vectors received market authorization from the European Medicine Agencies to treat lipoprotein lipase deficiency in patients, the safe, translational application of rAAV vectors in the clinics still remains hindered by the natural presence of neutralizing antibodies against the viral capsid proteins in the human population and by a possible dissemination of the vectors to nontarget tissues. To address these issues, the goal of the present proposal is to test the hypothesis that therapeutic rAAV (TGF-ß, SOX9) vectors may be delivered via coating onto biocompatible, solid poly(sodium styrene sulfonate) (pNaSS)-grafted poly(epsilon)-caprolactone (PCL) scaffolds as controlled gene delivery systems to safely, effectively, locally, and durably enhance the chondrogenic processes and mechanisms relevant of cartilage repair in natural, primary concentrated hMSCs in vitro, in a pre-translational osteochondral culture model, and in translational osteochondral defects in vivo. This project may offer new, effective therapies to enhance cartilage repair in patients in a close future.