Gene therapy studies, which began in the early 1980's, have now reached the point where critical importance of basic studies into the diseases and the biology associated with gene transfer have become widely acknowledged. In particular, studies on hemophilia B (factor IX deficiency) have greatly contributed to the understanding of gene transfer biology in general and have highlighted specific issues which must be systematically studied before safe and truly robust clinical human gene therapies can be developed. To date, most of these fundamental issues remain to be addressed. The studies detailed in this proposal will continue to focus study on hemophilia B by vigorously addressing selected critical issues and gaining insights into the basic biology underlying gene transfer. Studies proposed have three major aims centered on factor IX (FIX) as the model gene:
Aim 1, delineation of the biology and mechanisms involved in muscle- targeted gene transfer;
Aim 2, development of a robust FIX AAV (adeno-associated virus) - mediated gene transfer system;
Aim 3, characterization of the immune responses to IX, delivered as a purified protein and by gene transfer approaches, and development of methods for induces immune tolerance. Establishment of an extensively studied and mechanistically well- understood gene therapy for hemophilia B will serve as a model for future gene therapy studies, and will provide an exciting foundation for development of clinical therapies, not only for hematological and metabolic diseases requiring systemic or local delivery of gene products, but also for other diseases such as muscular disorders.
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