Mechanisms of distribution of mouse β-galactosidase in the adult GM1-gangliosidosis brain
Mechanisms of distribution of mouse β-galactosidase in the adult GM1-gangliosidosis brain
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DOI：
10.1038/gt.2008.149
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发表时间：
2009-02-01
期刊：
影响因子：
5.1
通讯作者：
Sena-Esteves, M.
中科院分区：
文献类型：
--
作者：
Broekman, M. L. D.;Tierney, L. A.;Sena-Esteves, M.
神经节苷脂沉积症是由常染色体隐性缺陷的溶酶体酸性β-半乳糖苷酶(β-GAL)缺乏引起的一种溶酶体贮积性疾病(LSD)。这会导致GM1-神经节苷脂及其去唾液酸衍生物GA1在中枢神经系统(CNS)积聚，并导致进行性神经变性。治疗性AAV介导的LSD基因脑内传递在几个动物模型中被证明是非常成功的。GM1-神经节苷脂中毒也是AAV介导的中枢神经系统基因治疗的首选候选基因。由于全球神经病理学是这种疾病最严重的形式，治疗干预需要实现BGAL在整个中枢神经系统的分布。因此，仔细考虑给药途径和靶结构，从哪里可以产生代谢活性酶，释放和分布在整个中枢神经系统，是必要的。本研究的目的是通过海马区注射编码BGAL的AAV载体，研究BGAL在成年GM1神经节苷脂中毒小鼠脑内的分布模式和机制。我们发现了三种不同的机制导致其在脑内的分布：(1)扩散；(2)产生部位的轴突在神经元内的运输；(3)脑脊液在Virchow-Robin的血管周围空间流动。此外，我们还发现了载体编码的mRNA轴突运输的证据。
GM1-gangliosidosis is a lysosomal storage disease (LSD) caused by an autosomal recessive deficiency of lysosomal acid beta-galactosidase (beta gal). This leads to accumulation of GM1-ganglioside and its asialo derivative GA1 in the central nervous system (CNS), and progressive neurodegeneration. Therapeutic AAV-mediated gene delivery to the brain for LSDs has proven very successful in several animal models. GM1-gangliosidosis is also a prime candidate for AAV-mediated gene therapy in the CNS. As global neuropathology characterizes the most severe forms of this disease, therapeutic interventions need to achieve distribution of bgal throughout the entire CNS. Therefore, careful consideration of routes of administration and target structures from where metabolically active enzyme can be produced, released and distributed throughout the CNS, is necessary. The goal of this study was to investigate the pattern and mechanism of distribution of bgal in the adult GM1-gangliosidosis mouse brain upon hippocampal injection of an AAV vector-encoding bgal. We found evidence that three different mechanisms contribute to its distribution in the brain: (1) diffusion; (2) axonal transport within neurons from the site of production; (3) CSF flow in the perivascular space of Virchow-Robin. In addition, we found evidence of axonal transport of vector-encoded mRNA.