BASIC STUDIES ON ETIOLOGY, PATHOGENESIS &THERAPY OF METABOLIC STORAGE DISORDERS

Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

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.