Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Apr 1;99(7):1596–1605. doi: 10.1172/JCI119322

Murine mucopolysaccharidosis type VII: long term therapeutic effects of enzyme replacement and enzyme replacement followed by bone marrow transplantation.

M S Sands 1, C Vogler 1, A Torrey 1, B Levy 1, B Gwynn 1, J Grubb 1, W S Sly 1, E H Birkenmeier 1
PMCID: PMC507979  PMID: 9120003

Abstract

We demonstrated previously that short term administration of recombinant beta-glucuronidase to newborn mice with mucopolysaccharidosis type VII reduced lysosomal storage in many tissues. Lysosomal storage accumulated gradually after cessation of enzyme replacement therapy. Mice alive at 1 yr of age had decreased bone deformities and less lysosomal storage in cortical neurons. Here we compare the effects of long term enzyme replacement initiated either at birth or at 6 wk of age, and of enzyme administration initiated at birth followed by syngeneic bone marrow transplantation (BMT) at 5 wk of age. Several mice from each treatment group lived to at least 1 yr of age. Liver and spleen samples had beta-glucuronidase levels ranging from 2.4 to 19.8% of normal and showed a parallel decrease in lysosomal storage. The combination of enzyme replacement therapy followed by BMT reduced lysosomal distension in meninges, corneal fibroblasts, and bone when compared with treatment with enzyme alone. Mice treated at birth had less lysosomal storage in some neurons of the brain and the skeletal dysplasia was less severe when compared to mice whose treatment was delayed until 6 wk of age. We conclude that both enzyme replacement alone and early enzyme replacement followed by BMT have long term positive effects on murine mucopolysaccharidosis type VII. In addition, treatment started at birth is far more effective than treatment initiated in young adults.

Full Text

The Full Text of this article is available as a PDF (651.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aguirre G., Raber I., Yanoff M., Haskins M. Reciprocal corneal transplantation fails to correct mucopolysaccharidosis VI corneal storage. Invest Ophthalmol Vis Sci. 1992 Aug;33(9):2702–2713. [PubMed] [Google Scholar]
  2. Bastedo L., Sands M. S., Lambert D. T., Pisa M. A., Birkenmeier E., Chang P. L. Behavioral consequences of bone marrow transplantation in the treatment of murine mucopolysaccharidosis type VII. J Clin Invest. 1994 Sep;94(3):1180–1186. doi: 10.1172/JCI117434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berry C. L., Vogler C., Galvin N. J., Birkenmeier E. H., Sly W. S. Pathology of the ear in murine mucopolysaccharidosis type VII. Morphologic correlates of hearing loss. Lab Invest. 1994 Sep;71(3):438–445. [PubMed] [Google Scholar]
  4. Birkenmeier E. H., Barker J. E., Vogler C. A., Kyle J. W., Sly W. S., Gwynn B., Levy B., Pegors C. Increased life span and correction of metabolic defects in murine mucopolysaccharidosis type VII after syngeneic bone marrow transplantation. Blood. 1991 Dec 1;78(11):3081–3092. [PubMed] [Google Scholar]
  5. Birkenmeier E. H., Davisson M. T., Beamer W. G., Ganschow R. E., Vogler C. A., Gwynn B., Lyford K. A., Maltais L. M., Wawrzyniak C. J. Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency. J Clin Invest. 1989 Apr;83(4):1258–1266. doi: 10.1172/JCI114010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  7. Crawley A. C., Brooks D. A., Muller V. J., Petersen B. A., Isaac E. L., Bielicki J., King B. M., Boulter C. D., Moore A. J., Fazzalari N. L. Enzyme replacement therapy in a feline model of Maroteaux-Lamy syndrome. J Clin Invest. 1996 Apr 15;97(8):1864–1873. doi: 10.1172/JCI118617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fischer H. D., Gonzalez-Noriega A., Sly W. S. Beta-glucuronidase binding to human fibroblast membrane receptors. J Biol Chem. 1980 Jun 10;255(11):5069–5074. [PubMed] [Google Scholar]
  9. Gabel C. A., Goldberg D. E., Kornfeld S. Identification and characterization of cells deficient in the mannose 6-phosphate receptor: evidence for an alternate pathway for lysosomal enzyme targeting. Proc Natl Acad Sci U S A. 1983 Feb;80(3):775–779. doi: 10.1073/pnas.80.3.775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Glaser J. H., Sly W. S. Beta-glucuronidase deficiency mucopolysaccharidosis: methods for enzymatic diagnosis. J Lab Clin Med. 1973 Dec;82(6):969–977. [PubMed] [Google Scholar]
  11. Haskins M. E., Desnick R. J., DiFerrante N., Jezyk P. F., Patterson D. F. Beta-glucuronidase deficiency in a dog: a model of human mucopolysaccharidosis VII. Pediatr Res. 1984 Oct;18(10):980–984. doi: 10.1203/00006450-198410000-00014. [DOI] [PubMed] [Google Scholar]
  12. Hoogerbrugge P. M., Suzuki K., Suzuki K., Poorthuis B. J., Kobayashi T., Wagemaker G., van Bekkum D. W. Donor-derived cells in the central nervous system of twitcher mice after bone marrow transplantation. Science. 1988 Feb 26;239(4843):1035–1038. doi: 10.1126/science.3278379. [DOI] [PubMed] [Google Scholar]
  13. Krivit W., Pierpont M. E., Ayaz K., Tsai M., Ramsay N. K., Kersey J. H., Weisdorf S., Sibley R., Snover D., McGovern M. M. Bone-marrow transplantation in the Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI). Biochemical and clinical status 24 months after transplantation. N Engl J Med. 1984 Dec 20;311(25):1606–1611. doi: 10.1056/NEJM198412203112504. [DOI] [PubMed] [Google Scholar]
  14. Maréchal V., Naffakh N., Danos O., Heard J. M. Disappearance of lysosomal storage in spleen and liver of mucopolysaccharidosis VII mice after transplantation of genetically modified bone marrow cells. Blood. 1993 Aug 15;82(4):1358–1365. [PubMed] [Google Scholar]
  15. Matzner U., von Figura K., Pohlmann R. Expression of the two mannose 6-phosphate receptors is spatially and temporally different during mouse embryogenesis. Development. 1992 Apr;114(4):965–972. doi: 10.1242/dev.114.4.965. [DOI] [PubMed] [Google Scholar]
  16. 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. Nat Genet. 1993 Jun;4(2):154–159. doi: 10.1038/ng0693-154. [DOI] [PubMed] [Google Scholar]
  17. Moullier P., Maréchal V., Danos O., Heard J. M. Continuous systemic secretion of a lysosomal enzyme by genetically modified mouse skin fibroblasts. Transplantation. 1993 Aug;56(2):427–432. doi: 10.1097/00007890-199308000-00034. [DOI] [PubMed] [Google Scholar]
  18. Naumann G. Clearing of cornea after perforating keratoplasty in mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) N Engl J Med. 1985 Apr 11;312(15):995–995. doi: 10.1056/nejm198504113121520. [DOI] [PubMed] [Google Scholar]
  19. Olsen I., Muir H., Smith R., Fensom A., Watt D. J. Direct enzyme transfer from lymphocytes is specific. Nature. 1983 Nov 3;306(5938):75–77. doi: 10.1038/306075a0. [DOI] [PubMed] [Google Scholar]
  20. Pastores G. M., Sibille A. R., Grabowski G. A. Enzyme therapy in Gaucher disease type 1: dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months. Blood. 1993 Jul 15;82(2):408–416. [PubMed] [Google Scholar]
  21. Richards S. M., Olson T. A., McPherson J. M. Antibody response in patients with Gaucher disease after repeated infusion with macrophage-targeted glucocerebrosidase. Blood. 1993 Sep 1;82(5):1402–1409. [PubMed] [Google Scholar]
  22. Sands M. S., Barker J. E., Vogler C., Levy B., Gwynn B., Galvin N., Sly W. S., Birkenmeier E. Treatment of murine mucopolysaccharidosis type VII by syngeneic bone marrow transplantation in neonates. Lab Invest. 1993 Jun;68(6):676–686. [PubMed] [Google Scholar]
  23. Sands M. S., Birkenmeier E. H. A single-base-pair deletion in the beta-glucuronidase gene accounts for the phenotype of murine mucopolysaccharidosis type VII. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6567–6571. doi: 10.1073/pnas.90.14.6567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sands M. S., Erway L. C., Vogler C., Sly W. S., Birkenmeier E. H. Syngeneic bone marrow transplantation reduces the hearing loss associated with murine mucopolysaccharidosis type VII. Blood. 1995 Sep 1;86(5):2033–2040. [PubMed] [Google Scholar]
  25. Sands M. S., Vogler C., Kyle J. W., Grubb J. H., Levy B., Galvin N., Sly W. S., Birkenmeier E. H. Enzyme replacement therapy for murine mucopolysaccharidosis type VII. J Clin Invest. 1994 Jun;93(6):2324–2331. doi: 10.1172/JCI117237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Senior P. V., Byrne S., Brammar W. J., Beck F. Expression of the IGF-II/mannose-6-phosphate receptor mRNA and protein in the developing rat. Development. 1990 May;109(1):67–73. doi: 10.1242/dev.109.1.67. [DOI] [PubMed] [Google Scholar]
  27. Shull R. M., Hastings N. E., Selcer R. R., Jones J. B., Smith J. R., Cullen W. C., Constantopoulos G. Bone marrow transplantation in canine mucopolysaccharidosis I. Effects within the central nervous system. J Clin Invest. 1987 Feb;79(2):435–443. doi: 10.1172/JCI112830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Shull R. M., Kakkis E. D., McEntee M. F., Kania S. A., Jonas A. J., Neufeld E. F. Enzyme replacement in a canine model of Hurler syndrome. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12937–12941. doi: 10.1073/pnas.91.26.12937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sklar M. M., Kiess W., Thomas C. L., Nissley S. P. Developmental expression of the tissue insulin-like growth factor II/mannose 6-phosphate receptor in the rat. Measurement by quantitative immunoblotting. J Biol Chem. 1989 Oct 5;264(28):16733–16738. [PubMed] [Google Scholar]
  30. 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. 1973 Feb;82(2):249–257. doi: 10.1016/s0022-3476(73)80162-3. [DOI] [PubMed] [Google Scholar]
  31. Taylor R. M., Farrow B. R., Stewart G. J. Amelioration of clinical disease following bone marrow transplantation in fucosidase-deficient dogs. Am J Med Genet. 1992 Feb 15;42(4):628–632. doi: 10.1002/ajmg.1320420439. [DOI] [PubMed] [Google Scholar]
  32. Taylor R. M., Farrow B. R., Stewart G. J., Healy P. J. Enzyme replacement in nervous tissue after allogeneic bone-marrow transplantation for fucosidosis in dogs. Lancet. 1986 Oct 4;2(8510):772–774. doi: 10.1016/s0140-6736(86)90299-0. [DOI] [PubMed] [Google Scholar]
  33. Vogler C., Birkenmeier E. H., Sly W. S., Levy B., Pegors C., Kyle J. W., Beamer W. G. A murine model of mucopolysaccharidosis VII. Gross and microscopic findings in beta-glucuronidase-deficient mice. Am J Pathol. 1990 Jan;136(1):207–217. [PMC free article] [PubMed] [Google Scholar]
  34. Vogler C., Sands M. S., Levy B., Galvin N., Birkenmeier E. H., Sly W. S. Enzyme replacement with recombinant beta-glucuronidase in murine mucopolysaccharidosis type VII: impact of therapy during the first six weeks of life on subsequent lysosomal storage, growth, and survival. Pediatr Res. 1996 Jun;39(6):1050–1054. doi: 10.1203/00006450-199606000-00019. [DOI] [PubMed] [Google Scholar]
  35. Vogler C., Sands M., Higgins A., Levy B., Grubb J., Birkenmeier E. H., Sly W. S. Enzyme replacement with recombinant beta-glucuronidase in the newborn mucopolysaccharidosis type VII mouse. Pediatr Res. 1993 Dec;34(6):837–840. doi: 10.1203/00006450-199312000-00028. [DOI] [PubMed] [Google Scholar]
  36. Watson G., Felder M., Rabinow L., Moore K., Labarca C., Tietze C., Vander Molen G., Bracey L., Brabant M., Cai J. D. Properties of rat and mouse beta-glucuronidase mRNA and cDNA, including evidence for sequence polymorphism and genetic regulation of mRNA levels. Gene. 1985;36(1-2):15–25. doi: 10.1016/0378-1119(85)90065-4. [DOI] [PubMed] [Google Scholar]
  37. Wolfe J. H., Sands M. S., Barker J. E., Gwynn B., Rowe L. B., Vogler C. A., Birkenmeier E. H. Reversal of pathology in murine mucopolysaccharidosis type VII by somatic cell gene transfer. Nature. 1992 Dec 24;360(6406):749–753. doi: 10.1038/360749a0. [DOI] [PubMed] [Google Scholar]
  38. Yeager A. M., Brennan S., Tiffany C., Moser H. W., Santos G. W. Prolonged survival and remyelination after hematopoietic cell transplantation in the twitcher mouse. Science. 1984 Sep 7;225(4666):1052–1054. doi: 10.1126/science.6382609. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES