Hemophilia is a bleeding disorder that affects about 13,000 people in the United States. Two types of hemophilia have been identified, hemophilia A and hemophilia B, which result from the deficiency of clotting factor VIII and IX, required for blood coagulation. Current treatment of the hemophilic patients requires frequent factor VIII or factor IX replacements to prevent bleeding. Unfortunately, many patients are exposed to blood-borne diseases like hepatitis and AIDS. Gene therapy offers an opportunity to cure the disease by introducing genes capable of synthesizing sustained and therapeutic amount of clotting factors. Towards this goal we have proposed the use of novel gene transfer approaches to introduce factor IX gene in a variety of somatic tissues. We have previously shown that factor IX gene introduced in mouse muscle synthesizes sustained levels of factor IX protein for over an eighteen month period. We now plan to use adenoviral and adeno-associated viral (AAV) vectors to introduce factor IX genes directly into muscle and liver. The in vivo gene delivery approach overcomes the barriers of cell culture in vitro and subsequent transplantation in the animals. Once we have generated adenoviral and AAV-recombinant viruses containing factor IX gene, we will introduce them in hemophilic dogs to study if the requirement for transfusion upon bleeding episode is abrogated. We plan to generate viral vectors which will not elicit cytotoxic T-lymphocyte (CTL) response in infected animals. We also plan to generate a mouse where factor IX gene is deleted and use it as a model system to study the immunogenecity problems associated with adenoviral vectors. We will also generate factor VIII recombinants. Finally, if appropriate levels of sustained factor IX can be achieved in mice or hemophilic dogs, we will plan to submit clinical protocols for undertaking gene therapy of severe hemophilic patients. We believe that the experimental strategy proposed here will allow us to generate appropriate vectors for delivery of clotting factor genes in patients.
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