Restoration of normal lysosomal function in mucopolysaccharidosis type VII cells by retroviral vector-mediated gene transfer

Abstract

Retroviral vectors were constructed containing a rat β-glucuronidase cDNA driven by heterologous promoters. Vector-mediated gene transfer into human and canine β-glucuronidase-deficient mucopolysaccharidosis type VII fibroblasts completely corrected the deficiency in β-glucuronidase enzymatic activity. In primary cultures of canine mucopolysaccharidosis type VII retinal pigment epithelial cells, which contain large amounts of undegraded glycosaminoglycan substrates, vector correction restored normal processing of specific glycosaminoglycans in the lysosomal compartment. In canine mucopolysaccharidosis type VII bone marrow cells, β-glucuronidase was expressed at high levels in transduced cells. Thus, the vector-encoded β-glucuronidase was expressed at therapeutic levels in the appropriate organelle and corrected the metabolic defect in cells exhibiting the characteristic pathology of this lysosomal storage disorder.