Mechanisms of self-assembly temperature-sensitive polymers forenhanced rAAV-mediated gene transfer into human mesenchymalstem cells

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Damage to the articular cartilage is a prevalent, major unresolved problem in a variety of joint disorders including trauma and osteoarthritis (OA). Current therapeutic options to repair traumatic or OA cartilage are diverse, but none can fully restore the cartilage function. Gene therapy allows for a direct application of genes coding for therapeutic factors in sites of injury, resulting in a temporarily and spatially defined delivery of the candidate agent.Recombinant adeno-assciated viral vectors (rAAV) are particularly clinically adapted tools to achieve this goal.Important limitations to their use still include a relatively low efficacy of penetration (~ 13% of effective internalization upon vector-cell contact via the heparan sulphate proteoglycan cellular receptor), the presence of neutralizing antibodies against the viral capsid in individuals, and the possible presence of inhibitory anticoagulants (heparin) in samples.A potential approach to overcome these issues is to deliver rAAV via polymeric biomaterials in order to enhance the rate of vector transfer via different cell entry mechanisms.The goal of this project is to test the hypothesis that rAAV can be effectively encapsulated and released from micelles and hydrogels of poly-ethylene oxide (PEO) and poly-propylene oxide (PPO) triblock copolymers to target hMSCs and human articular chondrocytes as key cell populations involved in the processes of cartilage repair.The differential features (composition vs. structure) of these copolymers enables the obtaining of tunable rAAV delivery systems for achieving high and sustained levels of gene transfer.This strategy could constitute a new safe, effective tool for delivering of therapeutic candidates in localized sites of cartilage lesions as a means to improve the repair processes of this tissue.