Gene therapy strategies for Antigen-specific tolerance induction in vivo

Gene therapy is a very promising approach to cure many types of diseases that are otherwise incurable or difficult to treat. Unlike many therapies, gene therapy offers a true curative therapy that has the potential to dramatically improve the quality of life and longevity of the patient while also reducing the cost-burden of the health care system. A major limiting factor currently plaguing the success of this approach is the development of immune responses toward the gene delivered. Generally, immune responses to the encoded gene occur after a subset of lymphocytes known as T cells recognize the delivered gene as foreign and work to eliminate the cells expressing it. Understanding why this immune reaction occurs and developing means to counter act the immune-mediated clearance of the gene expressing cells will greatly improve the efficacy of this therapeutic mode. Here we will explore strategies to limit the development of T cell immune responses by investigating how tolerogenic viral vectors work, to determine the impact of the state of the immune system at the time of gene delivery in causing immune responses, and to develop a means to condition the immune system to promote T cell tolerance to the delivered gene. Overall, this work will improve our understanding of how the immune system at the time of delivery impacts the efficacy and how the innate regulatory mechanisms that promote tolerance generally can be modulated to increase the efficacy of gene therapy.