Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan.
Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan.
复制标题
成年 GM1 神经节苷脂沉积症小鼠的全身 AAV9 基因转移减少了 CNS 中的溶酶体储存并延长了寿命。
DOI：
10.1093/hmg/ddv168
复制
发表时间：
2015
影响因子：
3.5
通讯作者：
Sena-Esteves,Miguel
中科院分区：
文献类型：
--
作者：
Weismann,CaraM;Ferreira,Jennifer;Keeler,AllisonM;Su,Qin;Qui,Linghua;Shaffer,ScottA;Xu,Zuoshang;Gao,Guangping;Sena-Esteves,Miguel
神经节苷脂沉积症(GM1)是一种常染色体隐性遗传性溶酶体储存病，基因突变导致溶酶体酸性β-半乳糖苷酶(β-Gal)活性降低或缺失。β半乳糖缺乏会导致神经节苷脂在中枢神经系统积聚。GM1的特点是进行性神经功能下降，导致全身瘫痪、极度消瘦和死亡。在这项研究中，我们评价了腺相关病毒9-mβ半乳糖载体系统地注入成年β小鼠(−/−)1×1011和3×1011载体基因组(VG)的治疗效果。生化分析显示β半乳糖基转移酶在肝脏和血清中活性较高。在整个中枢神经系统中，适度的β半乳糖水平导致脑中GM1神经节苷脂含量降低36-76%，脊髓中GM1Gal含量降低75%-86%。3×1011vg剂量组动物的中枢神经系统组织学分析显示，β半乳糖的存在增加，溶酶体储存的清除贯穿大脑皮层、海马区、脑干和脊髓。这些区域的存储减少伴随着星形胶质细胞增多的显著减少。AAV9治疗可改善患者在多项运动功能和行为测试中的表现。此外，在3×1011vg的队列中，大多数GM1小鼠由于体重减轻而达到了人性化的终点，但仍保持了行走和饲养。重要的是，AAV9治疗组的中位生存期(316-576天)显著高于对照组(250-264天)。本研究表明，β-Gal在神经节苷脂增多症小鼠中枢神经系统中的适度广泛表达足以实现显著的生化影响，并在表型上改善和延长寿命。
GM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease where GLB1 gene mutations result in a reduction or absence of lysosomal acid β-galactosidase (βgal) activity. βgal deficiency leads to accumulation of GM1-ganglioside in the central nervous system (CNS). GM1 is characterized by progressive neurological decline resulting in generalized paralysis, extreme emaciation and death. In this study, we assessed the therapeutic efficacy of an adeno-associated virus (AAV) 9-mβgal vector infused systemically in adult GM1 mice (βGal−/−) at 1 × 1011or 3 × 1011vector genomes (vg). Biochemical analysis of AAV9-treated GM1 mice showed high βGal activity in liver and serum. Moderate βGal levels throughout CNS resulted in a 36–76% reduction in GM1-ganglioside content in the brain and 75–86% in the spinal cord. Histological analyses of the CNS of animals treated with 3 × 1011vg dose revealed increased presence of βgal and clearance of lysosomal storage throughout cortex, hippocampus, brainstem and spinal cord. Storage reduction in these regions was accompanied by a marked decrease in astrogliosis. AAV9 treatment resulted in improved performance in multiple tests of motor function and behavior. Also the majority of GM1 mice in the 3 × 1011vg cohort retained ambulation and rearing despite reaching the humane endpoint due to weight loss. Importantly, the median survival of AAV9 treatment groups (316–576 days) was significantly increased over controls (250–264 days). This study shows that moderate widespread expression of βgal in the CNS of GM1 gangliosidosis mice is sufficient to achieve significant biochemical impact with phenotypic amelioration and extension in lifespan.