New molecular therapies based on gene delivery and stem cells have significant potential for tissue engineering and regenerative medicine for numerous diseases. Before these approaches can succeed, however, a number of fundamental engineering challenges must be overcome.

Gene therapy, the introduction of genetic material to the cells of a patient for therapeutic benefit, has the potential to directly translate the basic knowledge derived from the Human Genome Project into therapeutic benefit. However, the vehicles or vectors that deliver therapeutic genes still require engineering for enhanced efficiency and safety. Our efforts are focused on modifying these vehicles at the molecular level to overcome the common dilemma faced by all: they did not evolve in nature to perform the therapeutic endeavors we ask of them. We have developed novel approaches to engineer several promising gene delivery vehicles, ones based upon adeno-associated viruses and lentiviruses. Specifically, we are developing directed evolution approaches, including novel library generation and high throughput selection methods, to overcome several challenges in vector performance. We will present progress in applying these approaches to enhance a number of viral properties, including viral production, mass transport through tissue, interactions with the immune system, and targeted gene delivery.