Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice

Abstract

Fabry disease is an X-linked metabolic disorder caused by a deficiency of ␣-galactosidase A (␣-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with ␣-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated ␣-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of ␣-Gal A ؊͞0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of ␣-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease.

Cellular and tissue distribution of intravenously administered agalsidase alfa

“…All mice were males aged 126-149 days. This animal model was previously described in detail [13][14][15]. A total of 12 GLA −/− mice were injected intravenously via the tail vein.…”

“…The standard fluorimetric assay for alpha-galactosidase A was performed on tissue extracts as described [15,17] using 5 mM 4-methylumbelliferyl-alpha-D-galacto-pyranoside (Research Products International, M65400) at pH 4.4 in the presence of 0.1 M N-acetylgalactosamine, a specific inhibitor of alpha-galactosidase B [18].…”

Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human Fabry fibroblasts and Fabry mice

“…Kulkarni; Ohshima et al 1997Ohshima et al , 1999 were used in this experiment according to the rules drawn up by the Animal Care Committee of our institute. Fabry mice were divided into five groups, i.e., an untreated Fabry group (Fabry/untreated group), a Fabry group administered agalsidase alfa and another administered agalsidase beta at 0.5 mg/kg body weight (Fabry/agalsidase-alfa/0.5 group and Fabry/agalsidase-beta/0.5 group, respectively), and a Fabry group administered agalsidase alfa and another administered agalsidase beta at 3.0 mg/kg body weight (Fabry/agalsidase-alfa/3.0 group and Fabry/agalsidase-beta/3.0 group, respectively).…”

Genomic abnormalities of the murine model of Fabry disease after disease-related perturbation, a systems biology approach

“…Histological evidence suggests many similarities with human Fabry disease, although some discordance is present (4,(11)(12)(13). One significant advantage of the murine model is the ability to investigate Fabry tissues such as the aorta and heart, which are generally inaccessible in clinical studies.…”