A novel oligonucleotide-mediated gene targeting technology (Chimeraplasty in concert with a delivery technology are proposed to demonstrate the feasibility of permanently correcting point mutations that cause hemophilia in animal models of the disease. Current treatments for hemophilia, which is caused by a deficiency in blood clotting factors, involve injections of factor concentrates. This treatment must be repeated periodically, since the genetic mutations that cause the disease have not been corrected. Preliminary results demonstrated that Chimeraplasty can effect specific sequence changes in several chromosomal genes at high frequency, a requirement for a technology that could revolutionize therapy by correcting mutations that cause disease. We propose to demonstrate that Chimeraplasty can be used to target the factor VIII and factor IX genes, which are frequently mutated in hemophilia patients. We also propose to develop and optimize the hepatocyte delivery system for use in mice and dogs. These developments will enable testing the effectiveness of Chimeraplasty to correct factor VIII and factor IX gene mutations that cause hemophilia in mice and dogs. Testing Chimeraplasty in these animal models will provide critical information about the potential of gene correction therapies. PROPOSED COMMERCIAL APPLICATIONS: Hemophilia represents a significant health care market with 20,000 cases of hemophilia A and B in the US and over 80,000 cases in Europe. Since the majority of mutations that cause hemophilia are point mutations, they would be potential targets for gene correction using Chimeraplasty. Gene correction therapy would be a novel alternative to current treatments that require repeated injections of clotting factor concentrates, which can cost $65,000 or more per year.
