Grant: Operating Grant: Industry-partnered Collaborative Research

The severe inherited bleeding disease, hemophilia A, results in frequent recurrent bleeding episodes unless the missing clotting factor, factor VIII, is replaced. Since the 1970s treatment has relied upon the intravenous infusion of factor VIII concentrates that were initially derived from donated human plasma, but since the late 1980s, has increasingly involved infusion of factor VIII produced by recombinant DNA technology. Although these treatments are effective and safe, there are still a number of significant limitations to current therapies. In this research proposal, we intend to work with industrial partners to develop and evaluate novel therapies for hemophilia A that will improve the clinical outcomes and quality of life of patients with this condition. Central to the significance of this proposal is the maintenance of a unique colony of hemophilia A dogs at Queen's University. These dogs recapitulate many of the features of the human disease and have been used on many occasions during the past three decades to provide crucial preclinical testing of the efficacy and safety of novel treatment strategies for hemophilia A. In the current proposal, three specific areas of investigation will be undertaken in collaboration with our industrial partners. In the first of these projects, we will assess the potential of enhancing the benefit of current factor VIII protein therapies through protein engineering strategies aimed at prolonging the circulating half-life of factor VIII. In the second group of studies we will evaluate the long-term safety of gene therapy mediated by adeno-associated viral vector delivery. Finally, we will evaluate two strategies for genetic modification of endothelial cells derived from hemophilic dogs. The first approach will use lentiviral vector-mediated gene transfer and the second involves a novel genome editing approach.