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 in mouse embryonic stem cells by homologous recombination. Although these mice showed a complete lack of AGA activity, they appeared clinically normal at 10 weeks of age. Ultrastructural analysis studies revealed concentric lamellar inclusions in the kidneys and confocal microscopy using a fluorescent-labeled lectin specific for a-D-galactosyl residues showed accumulation of substrate in the kidneys as well as in the cultured fibroblasts. Lipid analysis revealed a marked accumulation of the substrate in the liver and the kidneys. Aging studies revealed progressive accumulation of the substrate with sub-clinical kidney pathology in 80 weeks old mice. Bone marrow transplant 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.We had earlier shown correction of AGA deficiency and accumulation of a-D-galactosyl residues in the cultured fibroblasts from the AGA null mice using biscistronic MDR vectors containing human AGA cDNA. These studies were extended for in vivo correction using liposomes as delivery vehicles.