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.

  • Research Article
  • Published:

Intraventricular administration of recombinant adenovirus to neonatal twitcher mouse leads to clinicopathological improvements

Gene Therapy volume 8, pages 1081–1087 (2001)Cite this article

Abstract

Twitcher mouse is a murine model of human globoid cell leukodystrophy (Krabbe disease), which is characterized by a genetic deficiency in galactocerebrosidase (GALC) activity. The nervous system is affected early and severely by demyelination in the white matter. So far, there is no effective treatment for Krabbe disease except bone marrow transplantation (BMT). However, BMT has inherent limitations such as unavailability of donors and graft-versus-host disease. In this study, we injected recombinant adenovirus encoding GALC into the lateral ventricle of twitcher mice at postnatal day 0 (PND 0) and the therapeutic effects were evaluated. Our results showed slight, but significant improvements in motor functions, body weight and twitching and a prolonged life span. In brain, GALC activity was increased to 15% that of normal littermates and psychosine concentration was decreased to 55% that of untreated twitcher mice at PND 15. The number of PAS-positive globoid cells in brain stem was also reduced significantly at PND 35. In contrast, when adenoviruses were injected to the twitcher mice at PND 15, almost no improvements were observed. These results demonstrate that the timing of treatment may be of great importance in Krabbe disease.

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. Duchen LW et al. Hereditary leucodystrophy in the mouse. The new mutant twitcher Brain 1980 103: 695–710

    Article  CAS  Google Scholar 

  2. Kobayashi T et al. The twitcher mouse: an enzymatically authentic model of human globoid cell leukodystrophy (Krabbe disease) Brain Res 1980 202: 479–483

    Article  CAS  Google Scholar 

  3. Taniike M, Suzuki K . Spacio-temporal progression of demyelination in twitcher mouse: with clinico-pathological correlation Acta Neuropathol 1994 88: 228–236

    Article  CAS  Google Scholar 

  4. Miyatake T, Suzuki K . Globoid cell leukodystrophy: additional deficiency of psychosine galactosidase Biochem Biophys Res Commun 1972 48: 538–543

    Article  CAS  Google Scholar 

  5. Igisu T, Suzuki K . Progressive accumulation of toxic metabolite in a genetic leukodystrophy Science 1984 224: 753–755

    Article  CAS  Google Scholar 

  6. Kobayashi T et al. Globoid cell leukodystrophy is a generalized galactosylsphingosine(psychosine) storage disease Biochem Biophys Res Commun 1987 144: 41–46

    Article  CAS  Google Scholar 

  7. Yeager AM et al. Prolonged survival and remyelination after hematopoietic cell transplantation in the twitcher mouse Science 1984 225: 1052–1054

    Article  CAS  Google Scholar 

  8. Suzuki K et al. The twitcher mouse: central nervous system pathology after bone marrow transplantation Lab Invest 1988 58: 302–309

    CAS  PubMed  Google Scholar 

  9. Krivit W et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy N Engl J Med 1998 338: 1119–1126

    Article  CAS  Google Scholar 

  10. Chen YQ, Rafi MA, de Gala G, Wenger DA . Cloning and expression of cDNA encoding human galactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy Hum Mol Genet 1993 2: 1841–1845

    Article  CAS  Google Scholar 

  11. Sakai N et al. Krabbe disease: isolation and characterization of a full-length cDNA for human galactocerebrosidase Biochem Biophys Res Commun 1994 198: 485–491

    Article  CAS  Google Scholar 

  12. Sakai N et al. Molecular cloning and expression of cDNA for murine galactocerebrosidase and mutation analysis of the twitcher mouse, a model of Krabbe's disease J Neurochem 1996 66: 1118–1124

    Article  CAS  Google Scholar 

  13. Suzuki K, Suzuki K . The twitcher mouse: a model for Krabbe disease and for experimental therapies Brain Pathol 1995 5: 249–258

    Article  CAS  Google Scholar 

  14. Takahashi H, Igisu H, Suzuki K, Suzuki K . The twitcher mouse: an ultrastructural study on the oligodendroglia Acta Neuropathol 1983 59: 159–166

    Article  CAS  Google Scholar 

  15. Hannun YA, Bell RM . Lysosphingolipids inhibit protein kinase C: Implications for the sphingolipidoses Science 1987 235: 670–674

    Article  CAS  Google Scholar 

  16. Hannun YA, Bell RM . Functions of sphingolipids and sphingolipid breakdown products in cellular regulation Science 1989 243: 500–507

    Article  CAS  Google Scholar 

  17. Kornfeld S, Mellman I . The biogenesis of lysosomes Annu Rev Cell Biol 1989 5: 483–525

    Article  CAS  Google Scholar 

  18. Rafi MA et al. Retroviral vector-mediated transfer of the galactocerebrosidase (GALC) cDNA leads to overexpression and transfer of GALC activity to neighboring cells Biochem Mol Med 1996 58: 142–150

    Article  CAS  Google Scholar 

  19. Daly TM et al. Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease Proc Natl Acad Sci USA 1999 96: 2296–2300

    Article  CAS  Google Scholar 

  20. Niwa H, Yamamura K, Miyazaki J . Efficient selection for high-expression transfectants with a novel eukaryotic vector Gene 1991 108: 193–200

    Article  CAS  Google Scholar 

  21. Miyake S et al. Efficient generation of recombinant adenovuruses using adenovirus DNA–terminal protein complex and a cosmid bearing the full-length virus genome Proc Natl Acad Sci USA 1996 93: 1320–1324

    Article  CAS  Google Scholar 

  22. Kanegae Y et al. Efficient gene activation in mammalian cells by using recombinant adenovirus expressing site-specific cre recombinase Nucleic Acids Res 1995 23: 3816–3821

    Article  CAS  Google Scholar 

  23. Kanegae Y, Makimura M, Saito I . A simple and efficient method for purification of infectious recombinant adenovirus Jpn J Med Sci Biol 1994 47: 157–166

    Article  CAS  Google Scholar 

  24. Matsushima GK et al. Absence of MHC class II molecules reduces CNS demyelination, microglial/macrophage infiltration, and twitching in murine globoid cell leukodystrophy Cell 1994 78: 645–656

    Article  CAS  Google Scholar 

  25. Raghavan S, Krusell A . Optimal assay conditions for enzymatic characterization of homozygous and heterozygous twitcher mouse Biochim Biophys Acta 1986 877: 1–8

    Article  CAS  Google Scholar 

  26. Matsumoto A et al. Transgenic introduction of human galactosylceramidase into twitcher mouse: significant phenotype improvement with a minimal expression Dev Brain Dysfunct 1997 10: 142–154

    Google Scholar 

  27. Lee VML, Page CD, Wu HL, Schlaepfer WW . Monoclonal antibodies to gel-excised glial filament protein and their reactivities with other intermediate filament protein J Neurochem 1984 42: 25–32

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr K Ohno (University of Tottori) for valuable advice on the HPLC method used in the measurement of psychosine and Dr I Saito and Dr Y Kanegae (University of Tokyo) for kindly providing the adenovirus vector. We thank Mr M Aoki (Laboratory Animal Center, The Jikei University School of Medicine) for technical assistance. We also would like to give special thanks to Dr K Suzuki (University of North Carolina) for critical reviewing of this manuscript.

Author information

Authors and Affiliations

  1. Department of Gene Therapy, Institute of DNA Medicine, Tokyo, Japan

    JS Shen, K Watabe, T Ohashi & Y Eto

  2. Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan

    T Ohashi & Y Eto

  3. Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan

    JS Shen & K Watabe

Authors
  1. JS Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Watabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Ohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Eto
    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

Shen, J., Watabe, K., Ohashi, T. et al. Intraventricular administration of recombinant adenovirus to neonatal twitcher mouse leads to clinicopathological improvements. Gene Ther 8, 1081–1087 (2001). https://doi.org/10.1038/sj.gt.3301495

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301495

Keywords

This article is cited by

Search

Advanced search

Quick links