Department of Medicine, University of Cambridge, Cambridge, UK.
Mol Ther. 2012 Aug;20(8):1489-500. doi: 10.1038/mt.2012.44. Epub 2012 Mar 27.
The GM2 gangliosidoses are fatal lysosomal storage diseases principally affecting the brain. Absence of β-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 β-hexosaminidase α (HEXA) and β (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 β-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.
GM2 神经节苷脂贮积症是主要影响大脑的致命溶酶体贮积病。桑德霍夫（Sandhoff）小鼠中缺乏β-己糖胺酶 A 和 B 的活性，导致神经功能障碍，并重现婴儿期急性泰萨氏症（Tay-Sachs disease，TSD）和桑德霍夫病（Sandhoff disease，SD）。将表达人β-己糖胺酶α（HEXA）和β（HEXB）亚基的重组腺相关病毒（recombinant adeno-associated viral vectors，rAAV），血清型 2/1，颅内共注射到 1 月龄桑德霍夫小鼠中，使 2 年生存率达到前所未有的水平，并预防了大脑和脊髓的疾病。通过向纹状体或小脑分别进行局部基因转移，分别解决了疾病的经典表现，包括痉挛（与震颤共济失调相反）。大量β-己糖胺酶同工酶的生物合成及其通过轴突、血管周和脑脊液（cerebrospinal fluid，CSF）空间以及扩散的全球分布，解释了持续的表型拯救——通过转导的脑实质、脉络丛上皮和背根神经节神经元长期表达蛋白。延长的存活期允许在未通过颅内载体递送的器官中表达隐匿性疾病。我们认为，将 rAAV 注入 CSF 空间并通过对流增强递送在几个战略部位进行脑实质内给药，将优化治疗许多影响神经系统的疾病中的神经退行性变。
