Abstract
A deficiency of β-glucuronidase (GUSB) causes the multisystem progressive degenerative syndrome, mucopolysaccharidosis (MPS) type VII (Sly disease)1, which includes mental retardation2. Animal homologues of MPS VII (ref. 3, 4) are models for testing somatic gene transfer approaches to treat the central nervous system in this and other lysosomal storage disorders5. Previous attempts to correct murine MPS VII by gene therapy have successfully treated lesions in some organs but not in the brain6–8. Other experimental modalities have forestalled some disease progression in the brain, but only if done at birth9,10, before the onset of severe lesions, when the animals are pheno-typically normal. We tested whether therapeutic amounts of GUSB could be delivered to the diseased adult brain by transplanting cells engineered to super-secrete the normal enzyme for export to surrounding neural tissues. Lysosomal distention was cleared from neurons and glial cells in the vicinity of the grafts, showing that the secreted enzyme could reach the diseased cells and reverse lesions in the severely diseased brain. The ability to correct established lesions will be important for the treatment of many lysosomal storage diseases affecting the brain, because most patients are not diagnosed until lesions are advanced enough to affect phenotype or developmental milestones in early childhood, and some forms of the diseases do not become apparent until later in life11.
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References
Sly, W.S., Quinton, B.A., McAlister, W.H. & Rimoin, D.L. Beta glucuronidase deficiency: Report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis. J. Pediatr. 82, 249–257 (1973).
Neufeld, E.F. & Muenzer, J. The mucopolysaccharidoses. in Metabolic Basis of Inherited Disease, 7th edn. (eds. Scriver, C.R., Beaudet, A.L, Sly, W.S. & Valle, D.) 2465–2494 (McCraw Hill, NY, 1995).
Haskins, M.E., Desnick, R.J., DiFerrante, N., Jezyk, P.F. & Patterson, D.F. Beta-glucuronidase deficiency in a dog: A model of mucopolysaccharidosis VII. Pediatr. Res. 18, 980–984 (1984).
Birkenmeier, E.H. et al. Murine mucopolysaccharidosis type VII: Characterization of a mouse with beta-glucuronidase deficiency. J. Clin. Invest. 83, 1258–1256 (1989).
Wolfe, J.H. & Sands, M.S. Murine mucopolysaccharidosis type VII: A model system for somatic gene therapy of the central nervous system, in Protocols for Gene Transfer in Neuroscience: Towards Gene Therapy of Neurologic Disorders . (eds. P.R. Lowenstein & L.W. Enquist) 263–274 (John Wiley and Sons, Essex, England, 1996).
Wolfe, J.H. et al. Reversal of pathology in murine mucopolysaccharidosis type VII by somatic cell gene transfer. Nature 360, 749–753 (1992).
Wolfe, J.H., Deshmane, S.L. & Fraser, N.W. Herpesvirus vector gene transfer and expression of beta-glucuronidase in the central nervous system of MPS VII mice. Nature Genet. 1, 379–384 (1992).
Moullier, P., Bohl, D., Heard, J.-M. & Danos, O. Correction of lysosomal storage in the liver and spleen of MPS VII mice by implantation of genetically modified skin fibroblasts. Nature Genet. 4, 154–159 (1993).
Sands, M.S. et al. Enzyme replacement therapy for murine mucopolysaccharidosis type VII. J. Clin. Invest 93, 2324–2331 (1994).
Snyder, E.Y., Taylor, R.M. & Wolfe, J.H. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 374, 367–370 (1995).
Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D. Metabolic Basis of Inherited Disease, 7th edn., Part 12, Lysosomal Enzymes, 2427–2839 (McGraw Hill, New York, 1995).
Taylor, R.M. & Wolfe, J.H. Cross-correction of beta-glucuronidase deficiency by retroviral vector-mediated gene transfer. Exp. Cell Res. 214, 606–613 (1994).
Wolfe, J.H. et al. High level expression and export of beta-glucuronidase from murine mucopolysaccharidosis VII cells corrected by a double-copy retrovirus vector. Gene Ther. 2, 70–78 (1995).
Fisher, L.J. & Gage, F.H. Grafting in the mammalian central nervous system. Physiol. Rev. 73, 583–616 (1993).
Flanagan, J.R. et al. Cloning of a negative transcription factor that binds to the upstream conserved region of Moloney murine leukemia virus. Mol. Cell. Biol. 12, 38–44 (1992).
Ohashi, T. et al. Efficient transfer and sustained high expression of the human glucocerebrosidase gene in mice and their functional macrophages following transplantation of bone marrow transduced by a retroviral vector. Proc. Natl. Acad. Sci. USA 89, 11332–11336 (1992).
Wolfe, J.H. et al. Restoration of normal lysosomal function in mucopolysaccharidosis type VII cells by gene transfer. Proc. Natl. Acad. Sci. USA 87, 2877–2881 (1990).
Kyle, J.W. et al. Correction of murine mucopolysaccharidosis VII by a human β-glucuronidase transgene. Proc. Natl. Acad. Sci. USA 87, 3914–3918 (1990).
Taylor, R.M. & Wolfe, J.H. Glycosaminoglycan storage in neonatal murine mucopolysaccharidosis type VII neurogltal cells and correction by |β-glucuronidase gene transfer. J. Neurochem. 68, 2079–2085 (1997).
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Taylor, R., Wolfe, J. Decreased lysosomal storage in the adult MPS VII mouse brain in the vicinity of grafts of retroviral vector-corrected fibroblasts secreting high levels of β-glucuronidase. Nat Med 3, 771–774 (1997). https://doi.org/10.1038/nm0797-771
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DOI: https://doi.org/10.1038/nm0797-771
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