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Intrathecal administration of AAV vectors for the treatment of lysosomal storage in the brains of MPS I mice

Gene Therapy volume 13, pages 917–925 (2006)Cite this article

Abstract

Mucopolysaccharidosis type I (MPS I) is caused by an inherited deficiency of α-L-iduronidase (IDUA). The result is a progressive, lysosomal storage disease with central nervous system (CNS) as well as systemic involvement. To target gene therapy to the CNS, recombinant adeno-associated virus (AAV) vectors carrying IDUA sequence were administered to MPS I mice via injection into cerebrospinal fluid. In contrast to intravenous administration, this intrathecal administration was effective in generating widespread IDUA activity in the brain, with the cerebellum and olfactory bulbs having highest activities. In general, IDUA levels correlated with vector dose, although this correlation was obscured in cerebellum by particularly high variability. High doses of vector (4 × 1010 particles) provided IDUA levels approaching or exceeding normal levels in the brain. Histopathology indicated that the number of cells with storage vacuoles was reduced extensively or was eliminated entirely. Elimination of storage material in Purkinje cells was particularly dramatic. A lower vector dose (2 × 109 particles) reduced both the number of storage cells and the extent of storage per cell, but the effect was not complete. Some perivascular cells with storage persisted, and this cell type appeared to be more resistant to treatment than neurons or glial cells. We conclude that intrathecal administration of AAV-IDUA delivers vector to brain cells, and that this route of administration is both minimally invasive and effective.

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Acknowledgements

We thank Susan Elliger, Amy Jess, Catherine McDonough and Dorothy Tabron for their technical assistance and expertise, and Dr Berna Atik for statistical analysis. This study was supported in part by a National Institutes of Health grant (R01 DK54285), CHORI and BioMarin Pharmaceuticals Inc.

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Authors and Affiliations

  1. Children's Hospital Oakland Research Institute, Oakland, CA, USA

    G Watson, J Bastacky & M Buddhikot

  2. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA

    P Belichenko & W C Mobley

  3. BioMarin Pharmaceuticals Inc., Novato, CA, USA

    S Jungles, M Vellard & E Kakkis

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Correspondence to G Watson.

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Watson, G., Bastacky, J., Belichenko, P. et al. Intrathecal administration of AAV vectors for the treatment of lysosomal storage in the brains of MPS I mice. Gene Ther 13, 917–925 (2006). https://doi.org/10.1038/sj.gt.3302735

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