Long-term correction of @entity2317 storage in Fabry XXXX by recombinant adeno-associated virus-mediated gene transfer.

@entity2317 @entity1 @entity17921 @entity64 @entity2315 @entity19 @entity177 @entity1573 @entity2314 @entity14079 @entity299 @entity10153
@entity2314 is an @entity14079 characterized by systemic and vascular accumulation of @entity2317 (Gb(3)) caused by a deficiency of the lysosomal enzyme alpha-galactosidase A ( @entity10153 ). The condition is associated with an increased morbidity and mortality due to @entity177 , @entity299 , and early onset of @entity64 . Hemizygous males are primarily affected clinically with variable expression in heterozygous females. Gene-therapy trials have been initiated recently in @entity10153 knockout @entity19 models of @entity2314 by using a variety of viral vectors. In the present investigation we administered single i.v. injections of 1 x 10(10) genomes of recombinant adeno-associated virus (rAAV) encoding the @entity1 @entity10153 gene driven by a modified @entity1573 @entity17921 promoter to @entity10153 knockout (Fabry) @entity19 . @entity19 were analyzed for expression of @entity10153 activity and Gb(3) levels in liver, kidney, heart, spleen, small intestine, lung, and brain. Administration of the rAAV- @entity17921 -hAGA vector resulted in stable expression of @entity10153 in organs of the Fabry @entity19 for >6 months. @entity10153 activity in the organs became equal to or higher than that of wild-type @entity19 . Accumulated Gb(3) in the liver, heart, and spleen was reduced to that of wild-type @entity19 with lesser but significant reductions in kidney, lung, and small intestine. Injection of the rAAV- @entity17921 -hAGA construct into skeletal muscle did not result in expression of @entity10153 in it or in other tissues. This study provides a basis for a simple and efficient gene-therapy approach for @entity1 with @entity2314 and is indicative of its potential for the treatment of other @entity2315 .
