Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy.
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.
Sevin
Caroline
C
Institut National de la Santé et de la Recherche Médicale U561, Université Paris V, 75014 Paris, France.
Benraiss
Abdellatif
A
Van Dam
Debby
D
Bonnin
Delphine
D
Nagels
Guy
G
Verot
Lucie
L
Laurendeau
Ingrid
I
Vidaud
Michel
M
Gieselmann
Volkmar
V
Vanier
Marie
M
De Deyn
Peter Paul
PP
Aubourg
Patrick
P
Cartier
Nathalie
N
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
D002553:Cerebroside-Sulfatase