Open AccessRestoration of normal lysosomal function in mucopolysaccharidosis type VII cells by retroviral vector-mediated gene transfer.
Author(s) -
John H. Wolfe,
Edward H. Schuchman,
Lawrence E. Stramm,
Elizabeth A. Concaugh,
Mark E. Haskins,
Gustavo D. Aguirre,
Donald F. Patterson,
Robert J. Desnick,
Eli Gilboa
Publication year - 1990
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.87.8.2877
Subject(s) - mucopolysaccharidosis , viral vector , beta glucuronidase , biology , lysosomal storage disease , glycosaminoglycan , heterologous , glucuronidase , genetic enhancement , microbiology and biotechnology , cell culture , gene , gene expression , biochemistry , enzyme , recombinant dna , genetics
Retroviral vectors were constructed containing a rat beta-glucuronidase cDNA driven by heterologous promoters. Vector-mediated gene transfer into human and canine beta-glucuronidase-deficient mucopolysaccharidosis type VII fibroblasts completely corrected the deficiency in beta-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, beta-glucuronidase was expressed at high levels in transduced cells. Thus, the vector-encoded beta-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.