MOUSE MODELS OF INHERITED METABOLIC DISORDERS

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Fabry disease is a fatal X-linked recessive metabolic disorder resulting from the deficient activity of the lysosomal enzyme, a-galactosidase A (AGA). In affected hemizygous males, the progressive deposition of substrate in lysosomes of vascular endothelial and smooth muscle cells causes occlusive vascular disease. To date, there is no specific treatment for this condition. Both enzyme replacement and gene therapy are under consideration, but carrying out these trials in human will be difficult and time-consuming. We have developed Fabry mouse model which will be valuable to develop such therapeutic regimes. This mouse model was generated by disrupting AGA genomic locus by gene targeting. These mice were deficient in AGA activity without any gross phenotype but displayed subclinical abnormalities such as concentric lamellar inclusions in the target tissues. Aging studies revealed progressive accumulation of the substrate and functional changes in the cardiac tissues. Bone marrow transplantation of the Fabry mice with bone marrow from wild type mice corrected the metabolic defects in most of the target tissues indicating its value in the clinical domain. Using retroviral gene therapy approach on bone marrow mononuclear cells from these mice and transplanting them into the Fabry mice indicated increase in the AGA activity and reduction in the lipid substrate levels in most of the target tissues of the transplanted mice 26 weeks post BMT. Similar studies using adeno vectors are cu