A single injection of an Adeno-associated virus vector into nuclei with divergent connections results in widespread vector distribution in the brain and global correction of a neurogenetic disease
A single injection of an Adeno-associated virus vector into nuclei with divergent connections results in widespread vector distribution in the brain and global correction of a neurogenetic disease
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DOI：
10.1523/jneurosci.2185-07.2007
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发表时间：
2007-09-12
影响因子：
5.3
通讯作者：
Wolfe, John H.
中科院分区：
文献类型：
--
作者：
Cearley, Cassia N.;Wolfe, John H.
神经遗传性疾病通常影响整个大脑的细胞。腺相关病毒（AAV）载体介导的正常cDNA的转移可以纠正注射部位的代谢缺陷，但整个脑的治疗需要广泛递送正常基因和/或蛋白质。目前的方法需要多次注射才能广泛分布。然而，一些AAV载体可以沿着与注射区域相关的神经元通路转运。因此，在中枢神经系统中广泛分散的系统为目标可能是从有限数量的网站基因传播的途径。我们在腹侧被盖区（VTA）测试了这一假设，该区域具有许多传出和传入投射。单次1 μ l注射导致载体基因组转运至脑远端的投射位点。与注射到纹状体相比，VTA注射导致大脑更多区域的酶水平更高。AAV-9血清型载体是传播最广泛的，但AAV-Rh。10和AAV-1也在VTA注射后转运。在MPS VII（粘多糖沉积症VII）（一种溶酶体贮积症）小鼠模型中检测了对神经遗传性疾病整体病变的影响。AAV-9 VTA注射后载体基因组的广泛分布导致酶产物通过周围细胞的分泌和摄取而进一步分布，并完全纠正整个脑中的储存病变。从单次注射到发达的大脑中的这种前所未有的校正水平提供了一种潜在的策略，以校正大量的大脑，同时最大限度地减少注射次数。
Neurogenetic disorders typically affect cells throughout the brain. Adeno-associated virus (AAV) vector-mediated transfer of a normal cDNA can correct the metabolic defects at the site of injection, but treatment of the entire brain requires widespread delivery of the normal gene and/or protein. Current methods require multiple injections for widespread distribution. However, some AAV vectors can be transported along neuronal pathways associated with the injected region. Thus, targeting widely dispersed systems in the CNS might be a pathway for gene dispersal from a limited number of sites. We tested this hypothesis in the ventral tegmental area (VTA), a region with numerous efferent and afferent projections. A single 1 mu l injection resulted in transport of the vector genome to projection sites in distal parts of the brain. When compared with injections into the striatum, the VTA injection resulted in higher enzyme levels in more regions of the brain. The AAV-9 serotype vector was the most widely disseminated, but AAV-Rh. 10 and AAV-1 were also transported after VTA injection. The effect on global lesions of a neurogenetic disease was tested in the mouse model of MPS VII (mucopolysaccharidosis VII), a lysosomal storage disorder. Widespread distribution of the vector genome after AAV-9 VTA injection resulted in even further distribution of the enzyme product, by secretion and uptake by surrounding cells, and complete correction of the storage lesions throughout the entire brain. This unprecedented level of correction from a single injection into the developed brain provides a potential strategy to correct a large volume of brain while minimizing the number of injections.