DEVELOPMENT OF LENTIVIRAL VECTORS FOR LIVER GENE TRANSFER AND APPLICATION TO EMOPHILIA GENE THERAPY

Hemophilia B is an inherited disease that results in spontaneous bleeding episodes, which, if left untreated, can be fatal. This highly debilitating disease is caused by mutations in the coagulation factor IX gene, and is amongst the most common bleeding disorders in the world, affecting 1 in 5000 men. In the developed world, recombinant factor IX replacements can be produced, and can provide considerable benefit to hemophiliacs. Unfortunately, these treatment are not without their drawbacks. For one, they do not offer an enduring form of therapy, and they require uncomfortable injections to be routinely administered. Sadly, more then 80% of hemophiliacs, mostly in the developing world, do not even have access to these treatments. For those who do have access, between 10–25% of them develop antibodies against the coagulation products, thereby negating the effectiveness of therapy. It is because of the shortcomings in current treatment strategies that gene therapy is widely regarded as an optimal approach for treating hemophilia B. The idea of gene therapy is to deliver a normal copy of a gene to an individual, in order to replace a disease-causing gene, and thereby target the disease at its cause. In this way, gene therapy provides a way for permanently curing a disease, a hitherto impossible feat. The goal of our work is to develop improved methods for delivering the factor IX gene to an individual. To do this, we will use viruses, nature’s own DNA delivery machines. Harmful material will be removed from the virus and replaced with the factor IX gene. To date, most attempts at gene therapy have been unsuccessful because the patient’s immune system has rejected the replacement gene, similar to the rejection of a virus. In our laboratory, we have recently developed a promising strategy for circumventing the immune response following delivery of the gene. The goal of the project here is to further develop this strategy, and others, to improve the success of gene transfer. The effectiveness of our novel system will be evaluated for the treatment of hemophilia B using both mouse and dog models of the disease. By creating a system that can effectively deliver a gene of interest into a host, our research will have important implications for the future development of gene therapy, and for the treatment of a variety of monogenic diseases, including hemophilia B.