Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy.

Abstract

Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal disease caused by a defect of the enzyme arylsulfatase A (ARSA) that disrupts the degradation of sulfatides (Sulf) in neurons and glial cells. Therapy for MLD requires active production of ARSA in the brain to prevent demyelination and neuronal damage, and efficient delivery of ARSA to act faster than disease progression, particularly in the rapidly progressive late infantile form. We used an adeno-associated virus serotype 5 (AAV5) vector to express the human ARSA gene in the brain of MLD mouse model. We achieved rapid, extensive and long-lasting expression of the recombinant ARSA in the brain, cerebellum and brainstem from at least 3 to 15 months post-injection. Analysis of the vector genome and ARSA distribution gave evidence for in vivo cross-correction of many untransduced neurons and astrocytes. ARSA delivery rapidly reversed Sulf storage and prevented neuropathological abnormalities and neuromotor impairment. We believe that AAV5-mediated brain delivery of ARSA is a potentially efficacious therapeutic strategy for MLD patients, especially for those with rapidly progressive form of the disease.

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@article{Sevin2006IntracerebralAV, title={Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy.}, author={Caroline Sevin and Abdellatif Benraiss and Debby Van Dam and Delphine Bonnin and Guy Nagels and Lucie V{\'e}rot and Ingrid Laurendeau and Michel Vidaud and Volkmar Gieselmann and Marie Th{\'e}r{\`e}se Vanier and Peter Paul De Deyn and Patrick A Aubourg and Nathalie Cartier}, journal={Human molecular genetics}, year={2006}, volume={15 1}, pages={53-64} }