Get access

Prevention of neuropathology in the mouse model of hurler syndrome

Authors

  • Nathalie Desmaris MSc,

    1. Unité Rétrovirus et Transfert Génétique, Département Neuroscience, Institut National de la Sante et de la Recherche Médicale U622, Institut Pasteur, Paris
    Search for more papers by this author
  • Lucie Verot MSc,

    1. Institut National de la Sante et de la Recherche Médicale U189, Faculté de Médecine Lyon-Sud, Oullins
    Search for more papers by this author
  • Jean Philippe Puech,

    1. Institut National de la Sante et de la Recherche Médicale U129, ICGM, Paris, France
    Search for more papers by this author
  • Catherine Caillaud MD,

    1. Institut National de la Sante et de la Recherche Médicale U129, ICGM, Paris, France
    Search for more papers by this author
  • Marie Thérèse Vanier MD,

    1. Institut National de la Sante et de la Recherche Médicale U189, Faculté de Médecine Lyon-Sud, Oullins
    Search for more papers by this author
  • Jean Michel Heard MD

    Corresponding author
    1. Unité Rétrovirus et Transfert Génétique, Département Neuroscience, Institut National de la Sante et de la Recherche Médicale U622, Institut Pasteur, Paris
    • Unité Rétrovirus et Transfert Génétique, Département Neuroscience, Institut Pasteur, 28, rue du Dr. Roux, 75015, Paris, France
    Search for more papers by this author

Abstract

A defect of the lysosomal enzyme α-L-iduronidase (IDUA) interrupts heparan and dermatan sulfate degradation and causes neuropathology in children with severe forms of mucopolysaccharidosis type I (MPSI, Hurler syndrome). Enzyme substitution therapy is beneficial but ineffective on the central nervous system. We could deliver the missing enzyme to virtually the entire brain of MPSI mice through a single injection of gene transfer vectors derived from adenoassociated virus serotype 2 (AAV2) or 5 (AAV5) coding for human IDUA. This result was reproducibly achieved with both vector types in 46 mice and persisted for at least 26 weeks. Success was more frequent, enzyme activity was higher, and corrected areas were broader with AAV5 than with AAV2 vectors. Treatment presumably reversed and certainly prevented the accumulation of GM2 and GM3 gangliosides, which presumably participates to neuropathology. Lysosomal distension, which already was present at the time of treatment, had disappeared from both brain hemispheres and was minimal in the cerebellum in mice analyzed 26 weeks after injection. This study shows that pathology associated with MPSI can be prevented in the entire mouse brain by a single AAV vector injection, providing a preliminary evaluation of the feasibility of gene therapy to stop neuropathology in Hurler syndrome. Ann Neurol 2004;56:68–76

Ancillary