Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy.
Hum Mol Genet
; 15(1): 53-64, 2006 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-16311251
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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
/
Terapia Genética
/
Expressão Gênica
/
Cerebrosídeo Sulfatase
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Vetores Genéticos
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Leucodistrofia Metacromática
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Hum Mol Genet
Ano de publicação:
2006
Tipo de documento:
Article