Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Inherited Disease
  • Published:

Long-term expression and transfer of arylsulfatase A into brain of arylsulfatase A-deficient mice transplanted with bone marrow expressing the arylsulfatase A cDNA from a retroviral vector

Gene Therapy volume 7, pages 1250–1257 (2000)Cite this article

Abstract

A deficiency of arylsulfatase A (ASA) results in the lysosomal lipid storage disease metachromatic leukodystrophy. The disease mainly affects the central nervous system causing a progressive demyelination. A therapeutic effect will depend on the delivery of the deficient enzyme to the central nervous system. We have transplanted ASA-deficient mice with bone marrow transduced with a retroviral vector expressing the human ASA cDNA. All transplanted animals initially showed high serum levels of human ASA. In 50% of the recipients high ASA serum levels were sustained for 12 months after transplantation. In the remaining mice, serum levels decreased rapidly to low or undetectable levels. ASA activity and immunoreactivity was detectable in all organs of animals with continuous levels of ASA in serum. Most notably, substantial amounts of ASA activity were transferred into the brain, reaching up to 33% of the normal tissue level. In contrast to peripheral organs, the amount of enzyme delivered to the brain did not correlate with ASA serum levels as an indicator of overexpression. This reveals that enzyme transfer to the brain is not due to endocytosis of serum ASA by endothelial cells, but rather to bone marrow-derived cells migrated into the brain.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Kolodny EH, Fluharty AL . Metachromatic leukodystrophy and multiple sulfatase deficiency: sulfatide lipidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease McGraw-Hill: New York 1995 pp 2693–2740

    Google Scholar 

  2. Salvetti A, Heard JM, Danos O . Gene therapy of lysosomal storage diseases Br Med Bull 1995 51: 106–122

    Article  CAS  PubMed  Google Scholar 

  3. Kornfeld S . Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors Annu Rev Biochem 1992 61: 307–330

    Article  CAS  PubMed  Google Scholar 

  4. Stewart K et al. Uptake of alpha-(L)-iduronidase produced by retrovirally transduced fibroblasts into neuronal and glial cells in vitro Gene Therapy 1997 4: 63–75

    Article  CAS  PubMed  Google Scholar 

  5. Neufeld EF . Lysosomal storage diseases Annu Rev Biochem 1991 60: 257–280

    Article  CAS  PubMed  Google Scholar 

  6. Penzien JM et al. Compound heterozygosity for metachromatic leukodystrophy and arylsulfatase A pseudodeficiency alleles is not associated with progresive neurological disease Am J Hum Genet 1993 52: 557–564

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Leinekugel P, Michel S, Conzelmann E, Sandhoff K . Quantitative correlation between the residual activity of beta-hexosaminidase A and arylsulfatase A and the severity of the resulting lysosomal storage disease Hum Genet 1992 88: 513–523

    Article  CAS  PubMed  Google Scholar 

  8. Barton NW et al. Replacement therapy for inherited enzyme deficiency – macrophage-targeted glucocerebrosidase for Gaucher's disease New Engl J Med 1991 324: 1464–1470

    Article  CAS  PubMed  Google Scholar 

  9. Walkley SU et al. Bone marrow transplantation corrects the enzyme defect in neurons of the central nervous system in a lysosomal storage disease Proc Natl Acad Sci USA 1994 91: 2970–2974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Taylor RM et al. Lysosomal enzyme replacement in neural tissues by allogeneic bone marrow transplantation following total lymphoid irradiation in canine fucosidosis Transplant Proc 1987 19: 2730–2734

    CAS  PubMed  Google Scholar 

  11. Hoogerbrugge PM et al. Allogeneic bone marrow transplantation for lysosomal storage diseases. The European Group for Bone Marrow Transplantation Lancet 1995 345: 1398–1402

    Article  CAS  PubMed  Google Scholar 

  12. Walkley S, Thrall M, March P, Wurzelmann S . Bone marrow transplantation in neuronal storage disorders Brain Pathol 1994 4: 460

    Google Scholar 

  13. Walkley SU, Dobrenis K . Bone marrow transplantation for lysosomal diseases Lancet 1995 345: 1382–1383

    Article  CAS  PubMed  Google Scholar 

  14. Hess B et al. Phenotype of arylsulfatase A-deficient mice: relationship to human metachromatic leukodystrophy Proc Natl Acad Sci USA 1996 93: 14821–14826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Matzner U, Habetha M, Gieselmann V . Retrovirally expressed human arylsulfatase A corrects the metabolic defect of arylsulfatase A-deficient mouse cells Gene Therapy 2000 7: 805–812

    Article  CAS  PubMed  Google Scholar 

  16. Schiffmann R et al. Transfer of the human glucocerebrosidase gene into hematopoietic stem cells of nonablated recipients: successful engraftment and long-term expression of the transgene Blood 1995 86: 1218–1227

    CAS  PubMed  Google Scholar 

  17. Schierau A et al. Interaction of arylsulfatase A with UDP-N-acetylglucosamine:lysosomal enzyme-N-acetylglucosamine-1-phosphotransferase J Biol Chem 1999 274: 3651–3658

    Article  CAS  PubMed  Google Scholar 

  18. Rommerskirch W et al. Restoration of arylsulphatase A activity in human-metachromatic-leucodystrophy fibroblasts via retroviral-vector-mediated gene transfer Biochem J 1991 280: 459–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ohashi T, Eto Y, Learish R, Barranger JA . Correction of enzyme deficiency in metachromatic leukodystrophy fibroblasts by retroviral-mediated transfer of the human arylsulphatase A gene J Inher Metab Dis 1993 16: 881–885

    Article  CAS  PubMed  Google Scholar 

  20. Wei JF, Wei FS, Samulski RJ, Barranger JA . Expression of the human glucocerebrosidase and arylsulfatase A genes in murine and patient primary fibroblasts transduced by an adeno-associated virus vector Gene Therapy 1994 1: 261–268

    CAS  PubMed  Google Scholar 

  21. Ohashi T, Matalon R, Barranger JA, Eto Y . Overexpression of arylsulfatase A gene in fibroblasts from metachromatic leukodystrophy patients does not induce a new phenotype Gene Therapy 1995 2: 363–368

    CAS  PubMed  Google Scholar 

  22. Ohashi T et al. Successful transduction of oligodendrocytes and restoration of arylsulfatase A deficiency in metachromatic leukodystrophy fibroblasts using an adenovirus vector Gene Therapy 1995 2: 443–449

    CAS  PubMed  Google Scholar 

  23. Learish R et al. Retroviral gene transfer and sustained expression of human arylsulfatase A Gene Therapy 1996 3: 343–349

    CAS  PubMed  Google Scholar 

  24. Sangalli A et al. Transduced fibroblasts and metachromatic leukodystrophy lymphocytes transfer arylsulfatase A to myelinating glia and deficient cells in vitro Hum Gene Ther 1998 9: 2111–2119

    Article  CAS  PubMed  Google Scholar 

  25. Krall WJ et al. Cells expressing human glucocerebrosidase from a retroviral vector repopulate macrophages and central nervous system microglia after murine bone marrow transplantation Blood 1994 83: 2737–2748

    CAS  PubMed  Google Scholar 

  26. Kennedy DW, Abkowitz JL . Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model Blood 1997 90: 986–993

    CAS  PubMed  Google Scholar 

  27. Einerhand MPW, Valerio D . Gene transfer into hematopoietic stem cells: prospects for human gene therapy Curr Top Microbiol Immunol 1992 177: 217–235

    CAS  PubMed  Google Scholar 

  28. Rynditch AV et al. The regional integration of retroviral sequences into the mosaic genomes of mammals Gene 1998 222: 1–16

    Article  CAS  PubMed  Google Scholar 

  29. Havenga M, Hoogerbrugge P, Valerio D, van Es HHG . Retroviral stem cell gene therapy Stem Cells 1997 15: 162–179

    Article  CAS  PubMed  Google Scholar 

  30. Hoogerbrugge PM, Valerio D . Bone marrow transplantation and gene therapy for lysosomal storage diseases Bone Marrow Transplant 1998 21: (Suppl.2) 34–36

    Google Scholar 

  31. Miranda SRP et al. Bone marrow transplantation in acid sphingomyelinase-deficient mice: engraftment and cell migration into the brain as a function of radiation, age, and phenotype Blood 1997 90: 444–457

    CAS  PubMed  Google Scholar 

  32. Cheng L et al. Sustained gene expression in retrovirally transduced, engrafting human hematopoietic stem cells and their lympho-myeloid progeny Blood 1998 92: 83–92

    CAS  PubMed  Google Scholar 

  33. Hawley RG, Lieu FHL, Fong AZC, Hawley TS . Versatile retroviral vectors for potential use in gene therapy Gene Therapy 1994 1: 136–138

    CAS  PubMed  Google Scholar 

  34. Baum H, Dodgson KS, Spencer B . The assay of aryl sulfatase A and B in human urine Clin Chim Acta 1959 4: 453–455

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank C Fischer for excellent technical assistance and Dr U Wottge for his help with irradiation of cells and mice. This work was supported by the Bundesministerium für Forschung und Technologie and by the Medical Faculty of the University of Tübingen (Fortune project no. 277).

Author information

Authors and Affiliations

  1. Institut für Physiologische Chemie, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany

    U Matzner & V Gieselmann

  2. Institut für Hirnforschung, Eberhard-Karls-Universität, Tübingen, Germany

    K Harzer

  3. Department of Human Genetics, University of Pittsburgh, PA, USA

    RD Learish & JA Barranger

Authors
  1. U Matzner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Harzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. RD Learish
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. JA Barranger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V Gieselmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matzner, U., Harzer, K., Learish, R. et al. Long-term expression and transfer of arylsulfatase A into brain of arylsulfatase A-deficient mice transplanted with bone marrow expressing the arylsulfatase A cDNA from a retroviral vector. Gene Ther 7, 1250–1257 (2000). https://doi.org/10.1038/sj.gt.3301232

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301232

Keywords

This article is cited by

Search

Advanced search

Quick links