title: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U561, Université Paris V, 75014 Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sevin
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Benraiss
authors.forename: Debby
authors.initials: D
authors.lastname: Van Dam
authors.forename: Delphine
authors.initials: D
authors.lastname: Bonnin
authors.forename: Guy
authors.initials: G
authors.lastname: Nagels
authors.forename: Lucie
authors.initials: L
authors.lastname: Verot
authors.forename: Ingrid
authors.initials: I
authors.lastname: Laurendeau
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gieselmann
authors.forename: Marie
authors.initials: M
authors.lastname: Vanier
authors.forename: Peter Paul
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier
mesh_terms: D000256:Adenoviridae; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002553:Cerebroside-Sulfatase / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D007966:Leukodystrophy, Metachromatic / Q000201:enzymology / Q000628:therapy*; D051379:Mice; D008817:Mice, Mutant Strains; D045442:Rotarod Performance Test
chemical_list: D002553:Cerebroside-Sulfatase