Gene Transfer Corrects Acute GM2 Gangliosidosis-Potential Therapeutic Contribution of Perivascular Enzyme Flow
Gene Transfer Corrects Acute GM2 Gangliosidosis-Potential Therapeutic Contribution of Perivascular Enzyme Flow
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DOI：
10.1038/mt.2012.44
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发表时间：
2012-08-01
影响因子：
12.4
通讯作者：
Cox, Timothy M.
中科院分区：
文献类型：
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作者：
Cachon-Gonzalez, M. Begona;Wang, Susan Z.;Cox, Timothy M.
GM 2神经节苷脂沉积症是主要影响大脑的致死性溶酶体贮积病。Sandhoff小鼠中β-氨基己糖苷酶A和B活性的缺乏导致神经功能障碍，并重现婴儿中的急性泰-萨二氏病（TSD）和Sandhoff病（SD）。将表达人β-氨基己糖苷酶a（HEXA）和β（HEKB）亚基的重组腺相关病毒载体（rAV）（血清型2/1）颅内共注射到1个月大的桑德霍夫小鼠体内，使小鼠前所未有地存活至2年，并预防了整个大脑的疾病和脊髓。疾病的典型表现，包括痉挛与震颤共济失调相反，分别通过将基因转移到纹状体或小脑来解决。β-氨基己糖苷酶同工酶的丰富生物合成及其通过轴突、血管周围和脑脊液（CSF）空间的全球分布以及扩散，解释了转导的脑实质、脉络丛上皮和背根神经节神经元提供纠正酶的持续表型拯救-长期蛋白表达。延长的生存期允许在颅内载体递送无法进入的器官中表达隐匿性疾病。我们认为，rAAV输注到CSF空间和脑实质内管理的对流增强交付在一些战略网站将最佳治疗神经退行性疾病的许多影响神经系统。
The GM2 gangliosidoses are fatal lysosomal storage diseases principally affecting the brain. Absence of beta-hexosaminidase A and B activities in the Sandhoff mouse causes neurological dysfunction and recapitulates the acute Tay-Sachs (TSD) and Sandhoff diseases (SD) in infants. Intracranial coinjection of recombinant adeno-associated viral vectors (rAAV), serotype 2/1, expressing human beta-hexosaminidase a (HEXA) and beta (HEXB) subunits into 1-month-old Sandhoff mice gave unprecedented survival to 2 years and prevented disease throughout the brain and spinal cord. Classical manifestations of disease, including spasticity-as opposed to tremor-ataxia-were resolved by localized gene transfer to the striatum or cerebellum, respectively. Abundant biosynthesis of beta-hexosaminidase isozymes and their global distribution via axonal, perivascular, and cerebrospinal fluid (CSF) spaces, as well as diffusion, account for the sustained phenotypic rescue-long-term protein expression by transduced brain parenchyma, choroid plexus epithelium, and dorsal root ganglia neurons supplies the corrective enzyme. Prolonged survival permitted expression of cryptic disease in organs not accessed by intracranial vector delivery. We contend that infusion of rAAV into CSF space and intraparenchymal administration by convection-enhanced delivery at a few strategic sites will optimally treat neurodegeneration in many diseases affecting the nervous system.