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.

  • Original Article
  • Published:

Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer

Gene Therapy volume 14, pages 405–414 (2007)Cite this article

Abstract

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by genetic deficiency of arylsulfatase A (ARSA) enzyme. Failure in catalyzing the degradation of its major substrate, sulfatide (Sulf), in oligodendrocytes and Schwann cells leads to severe demyelination in the peripheral (PNS) and central nervous system (CNS), and early death of MLD patients. The ARSA knockout mice develop a disease that resembles MLD but is milder, without significant demyelination in the PNS and CNS. We showed that adeno-associated virus serotype 5-mediated gene transfer in the brain of ARSA knockout mice reverses Sulf storage and prevents neuropathological abnormalities and neuromotor disabilities when vector injections are performed at a pre-symptomatic stage of disease. Direct injection of viral particles into the brain of ARSA knockout mice at a symptomatic stage results in sustained expression of ARSA, prevention of Sulf storage and neuropathological abnormalities. Despite these significant corrections, the treated mice continue to develop neuromotor disability. We show that more subtle biochemical abnormalities involving gangliosides and galactocerebroside are in fact not corrected.

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
Figure 7

Similar content being viewed by others

Abbreviations

AAV:

adeno-associated virus

ARSA:

arylsulfatase A

CNS:

central nervous system

ELISA:

enzyme-linked immunosorbent assay

ET:

early treated

GalC:

galactosylceramide

GALC:

galactocerebrosidase enzyme

GFAP:

glial fibrillary acidic protein

LSDs:

lysosomal storage diseases

LT:

late treated

MLD:

metachromatic leukodystrophy

M6P:

mannose-6-phosphate

PAS:

Periodic Acid Schiff

PFA:

paraformaldehyde

PNS:

peripheral nervous system

Sulf:

sulfatide.

References

  1. von Figura K, Gieselmann V, Jaeken J . Metachromatic leukodystrophy. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds). The Metabolic & Molecular Bases of Inherited Disease, 8th edn, McGraw-Hill Published: New York, 2001, pp 3695–3724.

    Google Scholar 

  2. Dupree JL, Popko B . Genetic dissection of myelin galactolipid function. J Neurocytol 1999; 28: 271–279.

    Article  CAS  Google Scholar 

  3. Pernber Z, Molander-Melin M, Berthold CH, Hansson E, Fredman P . Expression of the myelin and oligodendrocyte progenitor marker sulfatide in neurons and astrocytes of adult rat brain. J Neurosci Res 2002; 69: 86–93.

    Article  CAS  Google Scholar 

  4. Molander-Melin M, Pernber Z, Franken S, Gieselmann V, Mansson JE, Fredman P . Accumulation of sulfatide in neuronal and glial cells of arylsulfatase A deficient mice. J Neurocytol 2004; 33: 417–427.

    Article  CAS  Google Scholar 

  5. Hess B, Saftig P, Hartmann D, Coenen R, Lullmann-Rauch R, Goebel HH et al. Phenotype of arylsulfatase A-deficient mice: relationship to human metachromatic leukodystrophy. Proc Natl Acad Sci USA 1996; 93: 14821–14826.

    Article  CAS  Google Scholar 

  6. D'Hooge R, Coenen R, Gieselmann V, Lullmann-Rauch R, De Deyn PP . Decline in brainstem auditory-evoked potentials coincides with loss of spiral ganglion cells in arylsulfatase A-deficient mice. Brain Res 1999; 847: 352–356.

    Article  CAS  Google Scholar 

  7. D'Hooge R, Hartmann D, Manil J, Colin F, Gieselmann V, De Deyn PP . Neuromotor alterations and cerebellar deficits in aged arylsulfatase A-deficient transgenic mice. Neurosci Lett 1999; 273: 93–96.

    Article  CAS  Google Scholar 

  8. Saravanan K, Schaeren-Wiemers N, Klein D, Sandhoff R, Schwarz A, Yaghootfam A et al. Specific downregulation and mistargeting of the lipid raft-associated protein MAL in a glycolipid storage disorder. Neurobiol Dis 2004; 16: 396–406.

    Article  CAS  Google Scholar 

  9. Biffi A, De Palma M, Quattrini A, Del Carro U, Amadio S, Visigalli I et al. Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells. J Clin Invest 2004; 113: 1118–1129.

    Article  CAS  Google Scholar 

  10. Matzner U, Hartmann D, Lullmann-Rauch R, Coenen R, Rothert F, Mansson JE et al. Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations. Gene Therapy 2002; 9: 53–63.

    Article  CAS  Google Scholar 

  11. Matzner U, Harzer K, Learish RD, Barranger JA, Gieselmann V . 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 

  12. Matzner U, Herbst E, Hedayati KK, Lullmann-Rauch R, Wessig C, Schroder S et al. Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet 2005; 14: 1139–1152.

    Article  CAS  Google Scholar 

  13. Klein D, Schmandt T, Muth-Kohne E, Perez-Bouza A, Segschneider M, Gieselmann V et al. Embryonic stem cell-based reduction of central nervous system sulfatide storage in an animal model of metachromatic leukodystrophy. Gene Therapy 2006 (Epub ahead of print).

  14. Consiglio A, Quattrini A, Martino S, Bensadoun JC, Dolcetta D, Trojani A et al. In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected mice. Nat Med 2001; 7: 310–316.

    Article  CAS  Google Scholar 

  15. Sevin C, Benraiss A, Van Dam D, Bonnin D, Nagels G, Verot L et al. Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy. Hum Mol Genet 2006; 15: 53–64.

    Article  CAS  Google Scholar 

  16. Jurevics H, Hostettler J, Muse ED, Sammond DW, Matsushima GK, Toews AD et al. Cerebroside synthesis as a measure of the rate of remyelination following cuprizone-induced demyelination in brain. J Neurochem 2001; 77: 1067–1076.

    Article  CAS  Google Scholar 

  17. Muse ED, Jurevics H, Toews AD, Matsushima GK, Morell P . Parameters related to lipid metabolism as markers of myelination in mouse brain. J Neurochem 2001; 76: 77–86.

    Article  CAS  Google Scholar 

  18. Sands MS, Davidson BL . Gene therapy for lysosomal storage diseases. Mol Ther 2006; 13: 839–849.

    Article  CAS  Google Scholar 

  19. Peters C, Steward CG . Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone Marrow Transplant 2003; 31: 229–239.

    Article  CAS  Google Scholar 

  20. Rafi MA, Zhi Rao H, Passini MA, Curtis M, Vanier MT, Zaka M et al. AAV-mediated expression of galactocerebrosidase in brain results in attenuated symptoms and extended life span in murine models of globoid cell leukodystrophy. Mol Ther 2005; 11: 734–744.

    Article  CAS  Google Scholar 

  21. Chen F, Vitry S, Hocquemiller M, Desmaris N, Ausseil J, Heard JM . alpha-L-Iduronidase transport in neurites. Mol Genet Metab 2006; 87: 349–358.

    Article  CAS  Google Scholar 

  22. Luca T, Givogri MI, Perani L, Galbiati F, Follenzi A, Naldini L et al. Axons mediate the distribution of arylsulfatase A within the mouse hippocampus upon gene delivery. Mol Ther 2005; 12: 669–679.

    Article  CAS  Google Scholar 

  23. Suzuki K . Globoid cell leukodystrophy (Krabbe's disease): update. J Child Neurol 2003; 18: 595–603.

    Article  Google Scholar 

  24. Lin D, Fantz CR, Levy B, Rafi MA, Vogler C, Wenger DA et al. AAV2/5 vector expressing galactocerebrosidase ameliorates CNS disease in the murine model of globoid-cell leukodystrophy more efficiently than AAV2. Mol Ther 2005; 12: 422–430.

    Article  CAS  Google Scholar 

  25. d'Azzo A, Tessitore A, Sano R . Gangliosides as apoptotic signals in ER stress response. Cell Death Differ 2006; 13: 404–414.

    Article  CAS  Google Scholar 

  26. Svennerholm L, Vanier MT . Brain gangliosides in Krabbe disease. In: Aronson S, Volk BW (eds). Advance in Experimental Medicine and Biology. Plenum Press: New York, 1972, pp 499–514.

    Google Scholar 

  27. Suzuki K . Ganglioside patterns of normal and pathological brains. In: Aronson S, Volk BW (eds). Inborn Disorders of Sphingolipid Metabolism. Pergamon Press: Oxford, 1967, pp 215–230.

    Chapter  Google Scholar 

  28. Huang JQ, Trasler JM, Igdoura S, Michaud J, Hanal N, Gravel RA . Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases. Hum Mol Genet 1997; 6: 1879–1885.

    Article  CAS  Google Scholar 

  29. Desmaris N, Verot L, Puech JP, Caillaud C, Vanier MT, Heard JM . Prevention of neuropathology in the mouse model of Hurler syndrome. Ann Neurol 2004; 56: 68–76.

    Article  CAS  Google Scholar 

  30. Buccoliero R, Futerman AH . The roles of ceramide and complex sphingolipids in neuronal cell function. Pharmacol Res 2003; 47: 409–419.

    Article  CAS  Google Scholar 

  31. Ito JI, Young ZL, Masuda-Isobe M, Tanaka R . Suppression by gangliosides of polymerization of glial cytoskeletons prepared from rat astrocytes: a role of sialic acid moiety. Neurochem Int 1997; 31: 525–531.

    Article  CAS  Google Scholar 

  32. Dierks T, Dickmanns A, Preusser-Kunze A, Schmidt B, Mariappan M, von Figura K et al. Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. Cell 2005; 121: 541–552.

    Article  CAS  Google Scholar 

  33. Roeser D, Preusser-Kunze A, Schmidt B, Gasow K, Wittmann JG, Dierks T et al. A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. Proc Natl Acad Sci USA 2006; 103: 81–86.

    Article  CAS  Google Scholar 

  34. Takakusaki Y, Hisayasu S, Hirai Y, Shimada T . Coexpression of formylglycine-generating enzyme is essential for synthesis and secretion of functional arylsulfatase A in a mouse model of metachromatic leukodystrophy. Hum Gene Ther 2005; 16: 929–936.

    Article  CAS  Google Scholar 

  35. Salvetti A, Oreve S, Chadeuf G, Favre D, Cherel Y, Champion-Arnaud P et al. Factors influencing recombinant adeno-associated virus production. Hum Gene Ther 1998; 9: 695–706.

    Article  CAS  Google Scholar 

  36. Franklin BJ, Praxinos GT . The Mouse Brain in Stereotaxic Coordinates. Academic Press: New York, 1996.

    Google Scholar 

  37. Matzner U, Schestag F, Hartmann D, Lullmann-Rauch R, D'Hooge R, De Deyn PP et al. Bone marrow stem cell gene therapy of arylsulfatase A-deficient mice, using an arylsulfatase A mutant that is hypersecreted from retrovirally transduced donor-type cells. Hum Gene Ther 2001; 12: 1021–1033.

    Article  CAS  Google Scholar 

  38. Fujita N, Suzuki K, Vanier MT, Popko B, Maeda N, Klein A 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 

  39. Kyrklund T . Two procedures to remove polar contaminants from a crude brain lipid extract by using prepacked reversed-phase columns. Lipids 1987; 22: 274–277.

    Article  CAS  Google Scholar 

  40. Schott I, Hartmann D, Gieselmann V, Lullmann-Rauch R . Sulfatide storage in visceral organs of arylsulfatase A-deficient mice. Virchows Arch 2001; 439: 90–96.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A Salvetti, P Moullier and the vector core of the Association Française contre les Myopathies in Nantes for the preparation of the AAV vector. We express our gratitude to R D'Hooge who contributed to the initial phase of this work. We also thank Frieda Franck (Antwerp, Belgium) for her excellent collaboration and J Lopez for her technical assistance. This work was supported by grants from the European Leukodystrophy Foundation (ELA), the National Organization for Rare Disorders (NORD), the Association Française contre les Myopathies (AFM), the GIS-Institut des maladies rares, the Fédération pour la Recherche sur le Cerveau, the Fondation pour la Recherche Médicale (FRM) and the Fund for Scientific Research-Flanders (FWO grant G.0038.05), agreement between the Institute Born-Bunge and the University of Antwerp, Neurosearch Antwerp, Antwerp Medical Research Foundation, the Thomas Riellaerts Fund. DVD holds a postdoctoral position at the University of Antwerp.

Author information

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale Inserm U745, Laboratory of Molecular Genetics and Université ParisV, Paris, France

    C Sevin, A Benraiss, D Bonnin, F Fouquet, P Aubourg & N Cartier

  2. Inserm U499, Lyon and Fondation Gillet-Mérieux, University of Lyon and Lyon-Sud Hospital 69310 Pierre-Benite, France

    L Verot & M T Vanier

  3. Department of Biomedical Sciences, Laboratory of Neurochemistry and Behavior at Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

    D Van Dam, G Nagels & P P De Deyn

  4. Melsbroek and Department of Neurology, National MS Centre, University Hospital, Edegem, Belgium

    G Nagels

  5. Department of Physiological Chemistry, University of Bonn, Bonn, Germany

    V Gieselmann

  6. Department of Neurology and Memory Clinic, Middelheim General Hospital, Antwerp, Belgium

    P P De Deyn

Authors
  1. C Sevin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Verot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Benraiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Van Dam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Bonnin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Nagels
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F Fouquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V Gieselmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M T Vanier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P P De Deyn
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P Aubourg
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. N Cartier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Sevin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sevin, C., Verot, L., Benraiss, A. et al. Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer. Gene Ther 14, 405–414 (2007). https://doi.org/10.1038/sj.gt.3302883

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302883

Keywords

This article is cited by

Search

Advanced search

Quick links