In a collaborative study with investigators at the University of Oxford, UK, we are examining the effects of small molecular weight inhibitors of the formation of globotriaosylceramide in the murine analogue of Fabry disease created by scientists in DMNB and NIDCR. If these molecules prove effective in this model, their clinical effects will be evaluated in patients with Fabry disease. Since these molecules can cross the blood-brain barrier, it is anticipated that an investigation of the effect of inhibiting the formation of glucocerebroside and the toxic de-acylated derivative glucopsychosine, will be undertaken in patients with the neuronopathic forms of Gaucher disease.We have shown that bone-marrow transplantation causes a reduction of stored globotriaosylceramide in most of the organs and tissues of the murine model of Fabry disease. Bone-marrow stem and progenitor cells derived from patients with Fabry disease transduced with a retrovirus containing the human cDNA for alpha-galactosidase A are functionally corrected, and they express the enzyme for a long period of time. Moreover, the corrective alpha-galactosidase A is taken up by non-transduced bystander cells, and it is present in the circulation of experimental animals over an extended period. These experiments provide considerable incentive for gene therapy trials in patients with Fabry disease with transduced hematopoietic stem cells and bone-marrow mesenchymal stem cells. - Fabry Disease, Gaucher Disease; Inhibition of Sphingoglycolipid Formation; Gene Therapy - Human Subjects
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