Research Abstract:
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.
Selected Publications:
Miller DG, Wang P, Petek LM, et al. Gene targeting in vivo by adeno-associated virus vectors. Nature Biotech 2006 24:1022-1026.
Hofling AA, Devine S, Vogler C, Sands MS. Human CD34+ hematopoietic progenitor cell-directed lentiviral-mediated gene therapy in a xenotransplantation model of lysosomal storage disease. Mol Ther 2004 9:856-865.
Hennig A, Levy B, Ogilvie JM, et al. Intravitreal gene therapy reduces lysosomal storage in specific areas of the CNS in mucopolysaccharidosis VII mice. J Neurosci 2003 23:3302-3307.
Frisella A, O'Connor L, Vogler C, et al. Intracranial injection of recombinant adeno-associated virus improves cognitive function in a murine model of mucopolysaccharidosis type VII. Mol Ther 2001 3:351-358.
Daly T, Vogler C, Levy B, et al. Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease. Proc Natl Acad Sci USA 1999 96:2296-2300.
Last Updated: 10/16/2006 |