Widespread correction of lysosomal storage following intrahepatic injection of a recombinant adeno-associated virus in the adult MPS VII mouse.

Mucopolysaccharidosis type VII is a lysosomal storage disease caused by deficiency of the acid hydrolase beta-glucuronidase. MPS VII mice develop progressive lysosomal accumulation of glycosaminoglycans within multiple organs, including the brain. Using this animal model, we investigated whether gene transfer mediated by a recombinant adeno-associated virus (rAAV) type 2 vector is capable of reversing the progression of storage in adult mice. We engineered an rAAV2 vector to carry the murine beta-glucuronidase cDNA under the transcriptional direction of the human elongation factor-1alpha promoter. Intrahepatic administration of this vector in adult MPS VII mice resulted in stable hepatic beta-glucuronidase expression (473 +/- 254% of that found in wild-type mouse liver) for at least 1 year postinjection. There was widespread distribution of vector genomes and beta-glucuronidase within extrahepatic organs. The level of enzyme activity was sufficient to reduce lysosomal storage within the liver, spleen, kidney, heart, lung, and brain. Within selected regions of the brain, neuronal, glial, and perivascular cells had histopathologic evidence of reduced storage. Also, brain alpha-galactosidase and beta-hexosaminidase enzyme levels, secondarily elevated by the storage abnormality, were normalized. These data demonstrate that peripheral administration of an rAAV2 vector in adult MPS VII mice can lead to transgene expression levels sufficient for improvements in both the peripheral and the central manifestations of this disease.