Prevention of neuropathology in the mouse model of Hurler syndrome.

A defect of the lysosomal enzyme alpha-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.