Ex Vivo Gene Therapy of Hemophilia A

DESCRIPTION (provided by applicant): Hemophilia A is a bleeding disorder caused by mutations within the factor VIII (fVIII) gene that result in a deficiency of circulating fVIII activity. Current treatment for hemophilia relies on infusion of plasma-derived or recombinant fVIII to restore circulating fVIII activity. This form of therapy is 1) expensive, 2) hard to maintain due to the frequency and intravenous route of treatment, and 3) only offered to 30% of hemophilia A patients worldwide. The mission of Expression Therapeutics is to develop products that will improve the standard treatment of individuals with hemophilia A. Our technology is based on the identification of sequence elements within fVIII that can be modified to increase its biosynthesis. Gene therapy has the potential to cure hemophilia A. However in three previous clinical trials, the levels of circulating fVIII activity achieved were below that required for therapeutic efficacy and all trials ended following phase I. The goal of the studies proposed in this application is to demonstrate the effectiveness of fVIII high expression elements in a gene transfer-based treatment of hemophilia A. We propose to study the expression of several fVIII transgene constructs in vivo using the murine model of hemophilia A. Additionally, we will study fVIII biosynthesis from human stem/progenitor cells that are genetically modified using recombinant lentiviral vectors containing high expression fVIII transgenes. Demonstrating proof-of-concept that fVIII high expression elements are enabling to gene therapy of hemophilia A will represent a major milestone for Expression Therapeutics in the development of improved therapeutic treatments for hemophilia A. PROJECT NARATIVE Hemophilia A is a bleeding disorder caused by genetic mutation of a blood clotting factor, designated factor VIII (fVIII). Current treatment for hemophilia relies on infusion of plasma-derived or recombinant fVIII to restore circulating fVIII activity. This form of therapy is 1) expensive, 2) hard to maintain due to the frequency and intravenous route of treatment, and 3) only offered to 30% of hemophilia A patients worldwide. Therefore, the development of improved therapeutic treatments for hemophilia A, e.g. gene therapy, is warranted.