Liver gene transfer and hemophilia gene therapy

Gene therapy sets out to treat a disease by delivering a gene to a target tissue in the patients. Gene therapy may provide the only ultimate solution for genetic diseases in which the pathology is caused by the defect in a single gene. Over the years our group has developed a strategy to transfer genetic information into a cell based on virus-derived vectors (lentiviral vectors - LVs), highly efficient molecular shuttles that can introduce foreign DNA in host cells. We have recently shown the efficacy of our LV technology in transferring therapeutic genes in the liver upon a single administration. This maneuver can establish long-term correction of the coagulation disorder hemophilia B in mice affected by the disease, because the therapeutic gene product its secreted from the liver into the blood. Based on this success, we have also started evaluation in the large animal model of the same disease, the hemophilic dog, with encouraging results. We now propose to build on these achievements aiming at better characterizing the efficacy and safety profile of our gene therapy strategy towards clinical translation and in order to broaden its applications. We will thus thoroughly assess feasibility, efficacy and safety of our gene therapy strategy by expanding this study to more hemophilic dogs and developing improved LVs in order to enhance gene transfer and optimize the expression and activity of the therapeutic gene. Since LVs insert their genetic material into the genome, there is the risk of perturbation of the host cell genetic information leading to the initiation of a tumorigenic process (insertional mutagenesis). Thus, we will carefully address this risk and, if needed, further modify our LV platform and test improved designs that may alleviate such a risk. These studies will allow obtaining a comprehensive evaluation of the risk-benefit ratio of the LV technology for liver-directed gene therapy and will determine if its ready to cross the bridge to the clinical arena for a variety of monogenic diseases, including hemophilia A and B and mucopolysaccharidosis.