ADENOVIRUS-MEDIATED GENE-TRANSFER AND EXPRESSION OF HUMAN BETA-GLUCURONIDASE GENE IN THE LIVER, SPLEEN, AND CENTRAL-NERVOUS-SYSTEM IN MUCOPOLYSACCHARIDOSIS TYPE-VII MICE

Mucopolysaccharidosis type VII (Sly syndrome) is a lysosomal storage d isease caused by inherited deficiency of the lysosomal enzyme beta-glu curonidase. A murine model of this disorder has been well characterize d and used to study a number of forms of experimental therapies, inclu ding gene therapy. We produced recombinant adenovirus that expresses h uman beta-glucuronidase and administered this recombinant adenovirus t o beta-glucuronidase-deficient mice intravenously. The beta-glucuronid ase activities in liver and spleen were elevated to 40% and 20%, respe ctively, of the heterozygote enzymatic level at day 16. Expression per sisted for at least 35 days. Pathological abnormalities of these tissu es were also improved, and the elevated levels of urinary glycosaminog lycans were reduced in treated mice. However, the beta-glucuronidase a ctivity in kidney and brain was not significantly increased. After adm inistration of the recombinant adenovirus directly into the lateral ve ntricles of mutant mice, the beta-glucuronidase activity in crude brai n homogenates increased to 30% of heterozygote activity. Histochemical demonstration of beta-glucuronidase activity in brain revealed that t he enzymatic activity was mainly in ependymal cells and choroid. Howev er, in some regions, the adenovirus-mediated gene expression was also evident in brain parenchyma associated with vessels and in the meninge s. These results suggest that adenovirus-mediated gene delivery might improve the central nervous system pathology of mucopolysaccharidosis in addition to correcting visceral pathology.