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. We discovered several previuosly unknown characteristics of these diseases such as a primary immune defect and an unusual metabolic syndrome similar to starvation. A major focus of our current research is to determine the underlying molecular and cellular mechanisms leading to the CNS disease associated with this class of disease. This information has helped us to identify additional therapeutic targets and develop more rational approaches to therapy. 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) ex vivo and in vivo gene therapy, 2) direct protein replacement therapy, 3) bone marrow transplantation, and 4) small molecule drugs. 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 and human mesenchymal stem cells. Lysosomal storage is reduced in several key tissues after transplantation of the genetically modified stem cells into a murine xenotransplantation model of MPS VII. We are currently combining CNS-directed gene therapy with other disparate approaches (small molecule drugs, bone marrow transplantation, etc.) to enhance the efficacy of our therapies.
Selected Publications:
Macauley SL, Wozniak DF, Kieler C, Tan Y, Cooper J, Sands MS. Cerebellar pathology and motor dysfunction in the palmitoyl protein thioesterase-1-deficient mouse. Exp. Neurol. 2009 217: 124-135.
Woloszynek J, Coleman T, Semenkovich CF, Sands MS. Lysosomal dysfunction results in altered energy balance. J. Biol. Chem. 2007 282: 35765-35771.
Lin D, Donsante A, Macauley SL, Levy B, Vogler C, Sands MS. Central nervous system-directed AAV2/5-mediated gene therapy synergizes with bone marrow transplantation in the murine model of globoid-cell leukodystrophy. Mol. Ther. 2007 15: 44-52.
Donsante A, Miller DG, Vogler CA, Brundt B, Russell DW, Sands MS. AAV vector integration sites in mouse hepatocellular carcinoma. Science 2007 317: 477.
Meyerrose TE, Roberts MS, Ohlemiller KK, Vogler CA, Wirthlin L, Nolta JA, Sands MS. Lentiviral-transduced human mesenchymal stem cells persitently express therapeutic levels of enzyme in a xenotransplantation model of human disease. Stem Cells 2008 26: 1713-1722.
Last Updated: 06/29/2009 |