Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy
Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy
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DOI：
10.1093/hmg/ddi425
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发表时间：
2006-01-01
影响因子：
3.5
通讯作者：
Cartier, N
中科院分区：
文献类型：
--
作者：
Sevin, C;Benraiss, A;Cartier, N
异染性脑白质营养不良（MLD）是一种神经退行性溶酶体疾病，由芳基硫酸酯酶A（ARSA）缺陷引起，该酶破坏神经元和神经胶质细胞中硫苷脂（Sulf）的降解。MLD的治疗需要在大脑中主动产生ARSA以防止脱髓鞘和神经元损伤，并有效递送ARSA以比疾病进展更快地起作用，特别是在快速进展的晚期婴儿型中。我们用腺相关病毒5型（AAV5）载体在MLD小鼠模型脑中表达人ARSA基因。我们在注射后至少3至15个月实现了重组ARSA在脑、小脑和脑干中的快速、广泛和持久表达。载体基因组和ARSA分布的分析为许多未转导的神经元和星形胶质细胞的体内交叉校正提供了证据。ARSA递送迅速逆转硫储存并防止神经病理学异常和神经运动损伤。我们认为，AAV5介导的ARSA脑递送是MLD患者的潜在有效治疗策略，特别是对于那些具有快速进展形式的疾病的患者。
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.