Direct central nervous system delivery provides enhanced protection following vector mediated gene replacement in a severe model of spinal muscular atrophy.
Direct central nervous system delivery provides enhanced protection following vector mediated gene replacement in a severe model of spinal muscular atrophy.
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DOI：
10.1016/j.bbrc.2011.11.121
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发表时间：
2012-01-06
影响因子：
3.1
通讯作者：
Lorson, Christian L.
中科院分区：
文献类型：
--
作者：
Glascock, Jacqueline J.;Shababi, Monir;Wetz, Mary J.;Krogman, Megan M.;Lorson, Christian L.
关键词：
脊髓性肌萎缩症（SMA）是一种常染色体隐性神经肌肉疾病，是婴儿死亡的主要遗传原因。SMA是由存活运动神经元-1 （SMN1）的纯合子缺失引起的。然而，SMA并不是由于SMN的完全缺失，而是由一个几乎相同的复制基因SMN2产生低水平的功能性全长SMN。尽管SMN普遍表达，但运动神经元优先受到低SMN水平的影响。最近，基因替代策略在SMA动物模型中显示出巨大的前景。在这项研究中，我们使用表达全长SMN cDNA的自互补腺相关病毒（scAAV）来比较严重SMA小鼠模型中两种不同的病毒传递途径。这是通过将scAAV9-SMN载体静脉注射（IV）或脑室内（ICV）注射到SMA小鼠中来实现的。与未治疗的小鼠相比，两种分娩方式都导致寿命和体重显著增加，其中有一亚群小鼠存活超过200天。然而，注射ICV的小鼠比注射ICV的小鼠体重明显增加。同样，生存分析表明，ICV治疗的小鼠比IV治疗的小鼠显示出更少的早期死亡。总的来说，本报告表明，传递途径是SMA基因治疗的关键组成部分。
Spinal Muscular Atrophy (SMA), an autosomal recessive neuromuscular disorder, is the leading genetic cause of infant mortality. SMA is caused by the homozygous loss of Survival Motor Neuron-1 (SMN1). SMA, however, is not due to complete absence of SMN, rather a low level of functional full-length SMN is produced by a nearly identical copy gene called SMN2. Despite SMN’s ubiquitous expression, motor neurons are preferentially affected by low SMN levels. Recently gene replacement strategies have shown tremendous promise in animal models of SMA. In this study, we used self-complementary Adeno Associated Virus (scAAV) expressing full-length SMN cDNA to compare two different routes of viral delivery in a severe SMA mouse model. This was accomplished by injecting scAAV9-SMN vector intravenously (IV) or intracerebroventricularly (ICV) into SMA mice. Both routes of delivery resulted in a significant increase in lifespan and weight compared to untreated mice with a subpopulation of mice surviving more than 200 days. However, the ICV injected mice gained significantly more weight than their IV treated counterparts. Likewise, survival analysis showed that ICV treated mice displayed fewer early deaths than IV treated animals. Collectively, this report demonstrates that route of delivery is a crucial component of gene therapy treatment for SMA.
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影响因子：
46.9
作者：
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影响因子：
64.5
作者：
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作者：
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通讯作者：
Lorson, Christian L.