GENE THERAPY FOR HEMOPHILIA A AND B

Salk Institute For Biological Studies, La Jolla CA

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Abstract

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 amounts of clotting factors. Towards this goal we have proposed the use of novel gene transfer approaches to introduce factor IX and factor VIII genes in vivo by adeno-associated viral (AAV) vectors and novel lentiviral vectors. The availability of factor IX and factor VIII deficient mice offers an excellent experimental model system. Initial results indicate that AAV vectors containing factor IX gene transcribed from a liver specific promoter upon injection into the portal vein of mice deficient in factor IX (factor IX "knockout") produce well above therapeutic levels of factor IX for over eight weeks. Similarly, intraportal injection of lentiviral vectors generating factor VIII into factor VIII "knockout" mice show production of therapeutic levels of factor VIII protein in plasma. We plan to introduce factor IX and factor VIII producing recombinant viruses in hemophilic dogs deficient in factor IX or factor VIII protein. We also propose to transduce hematopoietic stem cells for producing factor IX or VIII protein. Additionally, we will generate cell lines capable of producing high quality and safe recombinant vectors. We believe the proposed experiments will give us sufficient information to consider clinical protocols, the long term goal of this proposal. Finally, we believe that the knowledge gained from gene therapy of hemophilia will serve as an excellent model system for many genetic diseases.