Fabry disease: We have explored several therapeutic strategies to treat patients with Fabry disease using the alpha-galactosidase A knock-out animal model of Fabry disease created by the Developmental and Metabolic Neurology Branch, We found that bone marrow stem and progenitor cells that had been transduced with a retroviral vector containing the alpha-galactosidase A gene resulted in the secretion of significant amounts of this enzyme into the blood of recipient animals. This demonstration indicated that the enzyme might be available to all of the organs and tissues of the animal. This observation was followed by studies on the effect of infusions of the transduced cells on the quantity of ceramidetrihexoside in the organs of the murine analog. The amount of accumulated lipid was significantly reduced following administration of the gene-corrected cells. Together, these findings provide encouragement for the exploration of gene therapy for Fabry disease. Another approach under consideration for the treatment of patients with this disorder is inhibition of the synthesis of ceramidetrihexoside. This strategy has been called""""""""substrate depletion"""""""". When immortalized lymphoblasts derived from patients with Fabry disease were treated with a potent inhibitor of ceramidetrihexoside synthesis developed by collaboratorsat the University of Michigan, we observed that the quantity of ceramidetrihexoside was significantly reduced. This investigation was followed by an examination of the effect of a similar inhibitor of ceramidetrihexoside synthesis in the mouse model of Fabry disease. We observed striking reductions in the quantities of this lipid in all of the major organs of the treated mice. These findings suggest that substrate depletion may have a role in the management of Fabry disease, alone, or perhaps in concert with enzyme replacement or gene therapy. Mucolipidosis IV. We have discovered the gene that is mutated in patients with this devastating neurogenetic disorder. It codes for a previously unknown ion channel protein. The condition is therefore properly classified as a novel channelopathy. This discovery is essential for the development of rational approaches to the therapy of this condition. An immediate benefit from the discovery is the ability to provide genetic counseling to a number of families in which this disorder occurs.
| Shin, Sang H; Kluepfel-Stahl, Stefanie; Cooney, Adele M et al. (2008) Prediction of response of mutated alpha-galactosidase A to a pharmacological chaperone. Pharmacogenet Genomics 18:773-80 |
| Goldin, Ehud; Caruso, Rafael C; Benko, William et al. (2008) Isolated ocular disease is associated with decreased mucolipin-1 channel conductance. Invest Ophthalmol Vis Sci 49:3134-42 |
| Shen, Jin-Song; Meng, Xing-Li; Moore, David F et al. (2008) Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease endothelial cells. Mol Genet Metab 95:163-8 |
| Shen, Jin-Song; Edwards, Nancy J; Hong, Young Bin et al. (2008) Isofagomine increases lysosomal delivery of exogenous glucocerebrosidase. Biochem Biophys Res Commun 369:1071-5 |
| Shin, Sang-Hoon; Murray, Gary J; Kluepfel-Stahl, Stefanie et al. (2007) Screening for pharmacological chaperones in Fabry disease. Biochem Biophys Res Commun 359:168-73 |
| Shen, Jin-Song; Meng, Xing-Li; Schiffmann, Raphael et al. (2007) Establishment and characterization of Fabry disease endothelial cells with an extended lifespan. Mol Genet Metab 92:137-44 |
| Askari, Hasan; Kaneski, Christine R; Semino-Mora, Cristina et al. (2007) Cellular and tissue localization of globotriaosylceramide in Fabry disease. Virchows Arch 451:823-34 |
| Moore, David F; Kaneski, Christine R; Askari, Hasan et al. (2007) The cerebral vasculopathy of Fabry disease. J Neurol Sci 257:258-63 |
| Lonser, R R; Schiffman, R; Robison, R A et al. (2007) Image-guided, direct convective delivery of glucocerebrosidase for neuronopathic Gaucher disease. Neurology 68:254-61 |
| Yoshimitsu, M; Higuchi, K; Ramsubir, S et al. (2007) Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells. Gene Ther 14:256-65 |
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