Long-term correction of globotriaosylceramide storage in Fabry mice by recombinant adeno-associated virus-mediated gene transfer

AUTOR(ES)

Park, Jinhee

FONTE

The National Academy of Sciences

RESUMO

Fabry disease is an X-linked recessive inborn metabolic disorder characterized by systemic and vascular accumulation of globotriaosylceramide (Gb3) caused by a deficiency of the lysosomal enzyme α-galactosidase A (α-gal A). The condition is associated with an increased morbidity and mortality due to renal failure, cardiac disease, and early onset of stroke. Hemizygous males are primarily affected clinically with variable expression in heterozygous females. Gene-therapy trials have been initiated recently in α-gal A knockout mouse models of Fabry disease by using a variety of viral vectors. In the present investigation we administered single i.v. injections of 1 × 1010 genomes of recombinant adeno-associated virus (rAAV) encoding the human α-gal A gene driven by a modified chicken β-actin (CAG) promoter to α-gal A knockout (Fabry) mice. Transgenic mice were analyzed for expression of α-gal A activity and Gb3 levels in liver, kidney, heart, spleen, small intestine, lung, and brain. Administration of the rAAV-CAG-hAGA vector resulted in stable expression of α-gal A in organs of the Fabry mice for >6 months. α-Gal A activity in the organs became equal to or higher than that of wild-type mice. Accumulated Gb3 in the liver, heart, and spleen was reduced to that of wild-type mice with lesser but significant reductions in kidney, lung, and small intestine. Injection of the rAAV-CAG-hAGA construct into skeletal muscle did not result in expression of α-gal A in it or in other tissues. This study provides a basis for a simple and efficient gene-therapy approach for patients with Fabry disease and is indicative of its potential for the treatment of other lysosomal storage disorders.

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