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Widespread distribution of β-hexosaminidase activity in the brain of a Sandhoff mouse model after coinjection of adenoviral vector and mannitol

Gene Therapy volume 10, pages 1841–1849 (2003)Cite this article

Abstract

Sandhoff disease is a severe inherited neurodegenerative disorder resulting from deficiency of the β-subunit of hexosaminidases A and B, lysosomal hydrolases involved in the degradation of GM2 ganglioside and related metabolites. Currently, there is no viable treatment for the disease. Here, we show that adenovirus-mediated transfer of the β-subunit of β-hexosaminidase restored Hex A and Hex B activity after infection of Sandhoff fibroblasts. Gene transfer following intracerebral injection in a murine model of Sandhoff disease resulted in near-normal level of enzymatic activity in the entire brain at the different doses tested. The addition of hyperosmotic concentrations of mannitol to the adenoviral vector resulted in an enhancement of vector diffusion in the injected hemisphere. Adenoviral-induced lesions were found in brains injected with a high dose of the vector, but were not detected in brains injected with 100-fold lower doses, even in the presence of mannitol. Our data underline the advantage of the adjunction of mannitol to low doses of the adenoviral vector, allowing a high and diffuse transduction efficiency without viral cytotoxicity.

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Acknowledgements

This work was supported by grants from Vaincre les Maladies Lysosomales (VML). We thank the Vector Core of the University Hospital of Nantes supported by the Association Française contre les Myopathies (AFM) for providing the adenovirus vectors. We also acknowledge Jean Denni of Saint Vincent de Paul Hospital, Paris, and Jeanne C Lesbordes of Institut Cochin, Paris, for helpful technical assistance.

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Author notes

  1. C Drugan

    Present address: Department of Medical Biochemistry, University of Medicine and Pharmacy, Cluj, Romania

Authors and Affiliations

  1. Département Génétique, Laboratoire de Génétique, Développement et Pathologie Moléculaire, Institut Cochin (INSERM, CNRS, Paris V University), Paris, France

    C Bourgoin, C Drugan, L Poenaru & C Caillaud

  2. Department of Biochemical Sciences and Molecular Biotechnologies, University of Perugia, Perugia, Italy

    C Emiliani, B Tancini & A Orlacchio

  3. Institut de Génétique Moléculaire, Montpellier, CNRS UMR 5535, France

    E J Kremer

  4. Département de Neuropédiatrie, Unité de Neuropathologie, Hôpital Armand Trousseau, Paris, France

    A Gelot

  5. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada

    R A Gravel

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Bourgoin, C., Emiliani, C., Kremer, E. et al. Widespread distribution of β-hexosaminidase activity in the brain of a Sandhoff mouse model after coinjection of adenoviral vector and mannitol. Gene Ther 10, 1841–1849 (2003). https://doi.org/10.1038/sj.gt.3302081

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  • DOI: https://doi.org/10.1038/sj.gt.3302081

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