Pathophysiology and novel therapies for lysosomal storage diseases
The two main goals in my laboratory are to better understand the underlying pathophysiology of lysosomal storage diseases (LSD) and to develop effective therapies for this class of inherited metabolic disorder. Since many LSDs are rare, it has been difficult to determine the natural history of these diseases. Therefore, we use murine models to study the progression of these diseases. This information has helped us to both develop more rational approaches to therapy and to identify additional therapeutic targets. We use a combination of molecular, biochemical, immunologic, electrophysiologic, histologic and behavioral assays to fully understand the pathogenesis of these diseases. With respect to the second major goal of my lab, we have developed and evaluated a number of therapeutic approaches that have shown varying degrees of efficacy in our murine models of disease. These include: 1) direct protein replacement therapy with recombinant enzyme, 2) bone marrow transplantation and 3) ex vivo and in vivo gene therapy. We showed that intravenous and CNS injections of a recombinant adeno-associated virus (AAV) vector provides widespread systemic and cognitive correction. We also use HIV-based gene transfer vectors to target human hematopoietic stem cells (CD34+) isolated from patients with MPS VII. Lysosomal storage is reduced in several key tissues after transplantation of the genetically modified hematopoietic progenitor cells into a murine xenotransplantation model of MPS VII. These findings will form the basis for an anticipated gene therapy clinical trial.