Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy
Authors: Sevin, Caroline; Benraiss, Abdellatif; Van Dam, Debby; Bonnin, Delphine; Nagels, Guy; Verot, Lucie; Laurendeau, Ingrid; Vidaud, Michel; Gieselmann, Volkmar; Vanier, Marie; De Deyn, Peter Paul; Aubourg, Patrick; Cartier, Nathalie
Source: Human Molecular Genetics, Volume 15, Number 1, 1 January 2006 , pp. 53-64(12)
Publisher: Oxford University Press
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.
Document Type: Research article
Publication date: 2006-01-01
- Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics.
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- In this Subject: Biology , Biotechnology , Pathology , Genetics
- By this author: Sevin, Caroline ; Benraiss, Abdellatif ; Van Dam, Debby ; Bonnin, Delphine ; Nagels, Guy ; Verot, Lucie ; Laurendeau, Ingrid ; Vidaud, Michel ; Gieselmann, Volkmar ; Vanier, Marie ; De Deyn, Peter Paul ; Aubourg, Patrick ; Cartier, Nathalie