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Genetic Approaches to Tissue Repair

Genetic approaches for tissue repair and regeneration lie at the interface of two exciting fields—gene therapy and tissue engineering. As these two fields advance towards maturity, combining their successes may yield new and powerful therapeutic avenues. However, a number of challenges must still be overcome before this promise can translate into a therapeutic reality. Gene therapy for tissue regeneration is currently faced with a number of questions, and further research is required to elucidate the correct solutions for specific therapeutic applications. First, when tissue undergoes injury due to either disease or trauma, a choice must be made between rescuing the damaged cells or replacing them, and each path offers particular challenges. For cell rescue, the choices of the therapeutic gene and the mode of delivery will determine the outcome. For cell replacement, a new supply of cells, such as stem cells, must be identified, and the basic biology of their function and behavior must be sufficiently understood before we can most effectively coax them into integrating with and regenerating damaged tissue. The first major challenge is then the development of improved gene delivery vehicles. Earlier in the development of this field, gene delivery was most often conducted ex vivo. For example, delivery to the nervous system, our laboratory’s target tissue, often involved retroviral gene delivery of growth or neurotrophic factors to autologous fibroblasts or myoblasts, followed by grafting to the site of injury. Although this approach has recently entered clinical trials for Alzheimer’s disease, the development of efficient direct gene delivery vehicles is generally more attractive than the ex vivo use of these cell types due to reduced complexity and potentially equal chances for success. A number of vehicles, both viral and synthetic, are under development for direct gene transfer, although they vary widely in a number of properties including efficiency, immunogenicity, and sustained and regulatable expression of the transgene cargo. Even with the more successful adeno-associated and lentiviral vehicles, improvements in efficiency are still required, and careful quanti-