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:

Attenuation of ganglioside GM1 accumulation in the brain of GM1 gangliosidosis mice by neonatal intravenous gene transfer

Gene Therapy volume 10, pages 1487–1493 (2003)Cite this article

Abstract

A single intravenous injection with 4 × 107 PFU of recombinant adenovirus encoding mouse β-galactosidase cDNA to newborn mice provided widespread increases of β-galactosidase activity, and attenuated the development of the disease including the brain at least for 60 days. The β-galactosidase activity showed 2–4 times as high a normal activity in the liver and lung, and 50 times in the heart. In the brain, while the activity was only 10–20% of normal, the efficacy of the treatment was distinct. At the 30th day after the injection, significant attenuation of ganglioside GM1 accumulation in the cerebrum was shown in three out of seven mice. At the 60th day after the injection, the amount of ganglioside GM1 was above the normal range in all treated mice, which was speculated to be the result of reaccumulation. However, the values were still definitely lower in most of the treated mice than those in untreated mice. In the histopathological study, X-gal-positive cells, which showed the expression of exogenous β-galactosidase gene, were observed in the brain. It is noteworthy that neonatal administration via blood vessels provided access to the central nervous system because of the incompletely formed blood–brain barrier.

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 5
Figure 4

Similar content being viewed by others

References

  1. Birkenmeier EH et al. Increased life span and correction of metabolic defects in murine MPSVII after syngeneic bone marrow transplantation. Blood 1991; 78: 3081–3092.

    CAS  Google Scholar 

  2. Ohashi T et al. Adenovirus-mediated gene transfer and expression of human β-glucuronidase gene in the liver, spleen, and central nervous system in mucopolysaccharidosis type VII mice. Proc Natl Acad Sci USA 1997; 94: 1287–1292.

    Article  CAS  Google Scholar 

  3. Konfeld S . Trafficking of lysosomal enzyme. FASEB J 1987; 1: 462–468.

    Article  Google Scholar 

  4. Sands MS et al. Murine mucopolysaccharidosis type VII: long term therapeutic effects of enzyme replacement and enzyme replacement followed by bone marrow transplantation. J Clin Invest 1997; 99: 1596–1605.

    Article  CAS  Google Scholar 

  5. Kakkis ED, Muenzer J, Tiller GE, Waber L . Enzyme replacement therapy in mucopolysacharidosis I. N Engl J Med 2001; 344: 182–188.

    Article  CAS  Google Scholar 

  6. Hoogerbrugge PM et al. Allogenic bone marrow transplantation for lysosomal storage diseases. Lancet 1995; 345: 1398–1402.

    Article  CAS  Google Scholar 

  7. Suzuki K et al. The Twitcher mouse: central nervous system pathology after bone marrow transplantation. Lab Invest 1998; 58: 302–309.

    Google Scholar 

  8. Matzner U 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 Therapy 2000; 7: 1250–1257.

    Article  CAS  Google Scholar 

  9. Pastores GM, Sibille AR, Grabowski GA . Enzyme therapy in Gaucher disease type I: dosage efficacy and adverse and effects in 33 patients treated for 6 to 24 months. Blood 1993; 82: 408–416.

    CAS  PubMed  Google Scholar 

  10. Desnick RJ, Banikazemi M, Wasserstein M . Enzyme replacement therapy for Fabry disease, an inherited nephropathy. Clin Nephrol 2002; 57: 1–8.

    Article  CAS  Google Scholar 

  11. Imaizumi M et al. Long term effects of bone marrow transplantation for inborn errors of metabolism: a study of four patients with lysosomal storage disease. Acta Pediat Jpn 1994; 36: 30–36.

    Article  CAS  Google Scholar 

  12. Elliger SS et al. Elimination of lysosomal storage in brains of MPS VII mice treated by intrathecal administration of an adeno-associated virus vector. Gene Therapy 1999; 6: 1175–1178.

    Article  CAS  Google Scholar 

  13. Frisella WA et al. Intracranial injection of recombinant adeno-associated virus improves cognitive function in a murine model of mucopolysaccharidosis type VII. Mol Ther 2001; 3: 351–358.

    Article  CAS  Google Scholar 

  14. Shen JS, Watabe K, Ohashi T, Eto Y . Intraventricular administration of recombinant adenovirus to neonatal Twitcher mouse leads to clinicopatholgical improvements. Gene Therapy 2001; 8: 1081–1087.

    Article  CAS  Google Scholar 

  15. Sands MS et al. Syngenic bone marrow transplantation reduces hearing loss associated with murine mucopolysaccharidosis type VII. Blood 1995; 86: 2033–2040.

    CAS  Google Scholar 

  16. O'Connor LH et al. Enzyme replacement therapy for murine mucopolysaccharidosis type VII leads to improvements in behavior and auditory function. J Clin Invest 1998; 101: 1394–1400.

    Article  CAS  Google Scholar 

  17. Volger C et al. Enzyme replacement therapy in murine mucopolysaccharidosis type VII: neuronal and glial response to β-glucuronidase requires early inhibition of enzyme replacement therapy. Ped Res 1999; 45: 838–844.

    Article  Google Scholar 

  18. Day 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: 11288–11294.

    Article  Google Scholar 

  19. Day TM et al. Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer. Gene Therapy 2001; 8: 1291–1298.

    Article  Google Scholar 

  20. Suzuki Y, Oshima A, Nanba E . β-Galactosidase deficiency (β-galactosidosis): GM1 gangliosidosis and Morquio B disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. McGraw-Hill: New York, 2001, pp 3775–3803.

    Google Scholar 

  21. Stewart PA, Hayakawa EM . Interendothelial junctional change underlie the developmental ‘tightening’ of the blood–brain barrier. Dev Brain Res 1987; 32: 271–281.

    Article  Google Scholar 

  22. Matsuda J et al. Neurological manifestations of knockout mice with β-galactosidase deficiency. Brain Dev 1997; 19: 19–20.

    Article  CAS  Google Scholar 

  23. Matsuda J et al. β-Galactosidase-deficient mouse as an animal model for GM1-gangliosidosis. Glycoconjugate J 1997; 14: 729–736.

    Article  CAS  Google Scholar 

  24. He TC et al. A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 1998; 95: 2509–2514.

    Article  CAS  Google Scholar 

  25. Nanba E, Suzuki K . Molecular cloning of mouse acid β-galactosidase cDNA: sequence, expression of catalytic activity and comparison with human enzyme. Biochem Biophys Res Comm 1990; 173: 141–148.

    Article  CAS  Google Scholar 

  26. Suzuki K . Enzymatic diagnosis of sphingolipidosis. Methods Enzymol 1987; 138: 727–762.

    Article  CAS  Google Scholar 

  27. Bradford MM . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 255–260.

    Article  Google Scholar 

  28. Fujita N et al. Targeted disruption of the mouse sphingolipid activator protein gene: a complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids. Hum Mol Genet 1996; 5: 711–725.

    Article  CAS  Google Scholar 

  29. Hahn CN et al. Generalized CNS disease and massive GM1-ganglioside accumulation in mice defective in lysosomal acid β-galactosidase. Hum Mol Genet 1997; 6: 205–211.

    Article  CAS  Google Scholar 

  30. Svennerholm L . Estimation of sialic acids. II. A colorimetric resorcinol-hydrochloric acid method. Biochem Biophys Acta 1957; 24: 604–611.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Junichiro Matsuda at the National Institute of Infectious disease, Tokyo, for providing us β-galactosidase knockout mouse. We also thank Dr Kunihiko Suzuki in the University of North Carolina at Chapel Hill, and Dr Marie T Vanier in University of Lyon, France, for their critical readings of the manuscript and many helpful suggestions.

This work was supported by grants AT-11694306 and AT-11557060 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan

    N Takaura, T Yamano & A Tanaka

  2. Department of Neurobiology and Anatomy, Osaka City University Graduate School of Medicine, Osaka, Japan

    T Yagi & M Maeda

  3. Gene Research Center, Tottori University, Yonago, Japan

    E Nanba

  4. Department of Pediatrics, Takagi Hospital, Saitama, Japan

    A Oshima

  5. Pediatrics, Clinical Research Center, Nasu Institute for Developmental Disabilities, International University of Health and Welfare, Ohtawara, Japan

    Y Suzuki

Authors
  1. N Takaura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Yagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Nanba
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Yamano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Tanaka
    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

Takaura, N., Yagi, T., Maeda, M. et al. Attenuation of ganglioside GM1 accumulation in the brain of GM1 gangliosidosis mice by neonatal intravenous gene transfer. Gene Ther 10, 1487–1493 (2003). https://doi.org/10.1038/sj.gt.3302033

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302033

Keywords

This article is cited by

Search

Advanced search

Quick links