Abstract
Genetic defects of lysosomal hydrolases result in severe storage diseases and treatments based on enzyme replacement have been proposed. In mice lacking β–glucuronidase, which develop a disease homologous to human mucopolysaccharidosis type VII (Sly syndrome), we have used autologous implants of genetically–modified skin fibroblasts for the continuous in vivo production of the enzyme. The human β–glucuronidase cDNA was introduced with a retroviral vector into mutant mice skin fibroblasts grown in primary culture. Fourteen mutant mice were implanted intraperitoneally with these modified cells embedded into collagen lattices. All animals expressed β–glucuronidase from the vascularized neo–organs that developed after implantation and accumulated the enzyme in their tissues. A complete disappearance of the lysosomal storage lesions was observed in their liver and spleen.
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References
Neufeld, E.F. & Muenzer, J. in The metabolic basis of inherited disease (eds Scriver, C. J., Beaudet, A. L., Sly, W. S. & Valle, D.) 1565–1587 (Mc Graw-Hill, New York, 1989).
Hopwood, J.J. & Morris, C.P. The mucopolysaccharidoses: diagnosis, molecular genetics and treatment. Molec. biol. Med. 7, 381–404 (1990).
Jezyk, P.F., Haskins, M.E., Patterson, D.F., Mellman, W.J. & Greenstein, M. Mucopolysaccharidosis in a cat with aryl-sulfatase B deficiency: a model of Maroteaux-Lamy syndrome. Science 198, 834–836 (1977).
Haskins, M.E., Desnick, R.J., DiFerrante, N., Jezyk, P. & Patterson, D.F. Beta-glucuronidase deficiency in a dog: a model of mucopolysaccharidosis VII. Pediatr. Res. 18, 980–984 (1984).
Shull, R.M. et al. Bone marrow transplantation in canine mucopolysaccharidosis I. J. clin. Invest. 79, 435–443 (1987).
Birkenmeier, E.H. et al. Murine mucopolysaccharidosis type VII. Characterization of a mouse with b-glucuronidase deficiency. J. clin. Invest. 83, 1258–1266 (1989).
Vogler, C. et al. A murine model of mucopolysaccharidosis VII: Gross and microscopic findings in beta-glucuronidase-deficient mice. Am. J. Pathol. 136, 207–217 (1990).
Pfeffer, S.R. Targeting of proteins to the lysosome. Curr. Top. microbiol. Immunol. 170, 43–63 (1991).
Barton, N.W. et al. Replacement therapy for inherited enzyme deficiency — macrophage-targeted glucocerebrosidase for Gaucher's disease. New Engl. J. Med. 23, 1464–1470 (1991).
Moullier, P., Maréchal, V., Danos, O. & Heard, J.M. Continous systemic secretion of a lysosomal enzyme by genetically-modified mouse skin fibroblasts. Transplantation (in the press).
Hayashi, M., Nakajima, Y. & Fishman, W.H. The cytologic demonstration of β-glucuronidase employing naphtol AS-BI glucuronide and hexazonium pararosanilin; a preliminary report. J. Histochem. Cytochem 12, 293–297 (1963).
Birkenmeier, E.H. et al. Increased life span and correction of metabolic defects in murine MPS VII following syngeneic bone marrow transplantation. Blood 78, 3081–3092 (1991).
Wolfe, J.H., Deshmane, S.L. & Fraser, N.W. Herpesvirus vector gene transfer and expression of β-glucuronidase in the central nervous system of MPS VII mice. Nature Genet. 1, 379–384 (1992).
Saint-Louis, D. & Verma, I.M. An alternative approach to somatic cell gene therapy. Proc. natn. Acad. Sci. U.S.A. 85, 3150–3154 (1988).
Palmer, T.D., Rosman, G.J., Osborne, W.R.A. & Miller, A.D. Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate introduced genes. Proc. natn. Acad. Sci. U.S.A. 88, 1330–1334. (1991).
Scharfmann, R., Axelrod, J.H. & Verma, I.M. Long-term in vivo expression of retrovirus-mediated gene transfer in mouse fibroblast implants. Proc. natn. Acad. Sci. U.S.A. 88, 4626–4630 (1991).
Bell, E. et al. The reconstitution of living skin. J. invest. Dermatol. 81, 2–10 (1983).
Whitley, C.B., Ridnour, M.D., Draper, K.A., Dutton, C.M. & Neglia, J.P. Diagnostic test for mucopolysaccharidosis. I. Direct method for quantifying excessive urinary glycosaminoglycan excretion. Clin. Chem. 35, 374–379 (1989).
Yanagishita, M. & Hascall, V.C. Cell surface heparan sulfate proteoglycans. J. biol. Chem. 267, 9451–9454 (1992).
Krivit, W., Shapiro, E., Hoogerbrugge, P.M. & Moser, H.W. State of the art review: bone marrow transplantation treatment for storage diseases. Bone Marrow Transpl. 10, 87–97 (1992).
Wolfe, J.H. et al. Reversal of pathology in murine mucopolysaccharidosis type VII by somatic cell gene transfer. Nature 360, 749–753 (1992).
Danos, O. & Mulligan, R.C. Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges. Proc. natn. Acad. Sci. U.S.A. 85, 6460–6464 (1988).
Danos, O. in Practical Molecular Virology (ed. Collins, M.K.L) 17–27 (Humana Press, Clifton, New-Jersey, 1991).
Wright, W.E., Sasoon, D.A. & Lin, V.K. Myogenin, a factor regulating myogenesis, has a domain homologous to MyoD. Cell 56, 607–617 (1989).
Thompson, J.A. et al. Site-directed neovessel formation in vivo. Science 241, 1349–1352 (1988).
Glaser, J.H. & Sly, W.S. β-glucuronidase deficiency mucopolysaccharidosis: methods for enzymatic diagnosis. J. lab clin. Med. 82, 969–977 (1973).
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Moullier, P., Bohl, D., Heard, JM. et al. Correction of lysosomal storage in the liver and spleen of MPS VII mice by implantation of genetically modified skin fibroblasts. Nat Genet 4, 154–159 (1993). https://doi.org/10.1038/ng0693-154
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DOI: https://doi.org/10.1038/ng0693-154
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