Global CNS Transduction of Adult Mice by Intravenously Delivered rAAVrh.8 and rAAVrh.10 and Nonhuman Primates by rAAVrh.10
Global CNS Transduction of Adult Mice by Intravenously Delivered rAAVrh.8 and rAAVrh.10 and Nonhuman Primates by rAAVrh.10
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DOI：
10.1038/mt.2014.68
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发表时间：
2014-07-01
影响因子：
12.4
通讯作者：
Gao, Guangping
中科院分区：
文献类型：
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作者：
Yang, Bin;Li, Shaoyong;Gao, Guangping
一些重组腺相关病毒（recombinant adeno-associated viruses，rAAV）可以穿过新生儿血脑屏障（blood-brain barrier，BBB）并有效地感染中枢神经系统（central nervous system，CNS）细胞。然而，在成人CNS中，通过全身递送的rAAV的转导水平显著降低，限制了它们用于CNS基因治疗的潜力。在这里，我们的特点是12个不同的rAAVEGFPs在成年小鼠中枢神经系统静脉内输送。我们表明，跨越成人血脑屏障和实现广泛的中枢神经系统转导的能力是一个共同的特点AAV血清型测试。值得注意的是，rAAVrh.8是用于在临床重要区域（例如皮质、尾壳核、海马、胼胝体和黑质）中神经胶质和神经元细胞类型的稳健全局转导的领先载体。与其他主要载体相比，它还显示出减少的外周组织向性。此外，我们评估了rAAVrh.10与和没有microRNA（miRNA）调节的表达从外周组织的系统性基因递送到中枢神经系统在绒猴去靶。我们的研究结果表明，rAAVrh.8，沿着rh.10和9，最有希望开发新的治疗策略，以治疗成人患者群体的神经系统疾病。此外，全身递送的rAAVrh.10可以有效地抑制CNS，并且其转基因表达可以在成年绒猴中被内源性miRNA限制在外周中。
Some recombinant adeno-associated viruses (rAAVs) can cross the neonatal blood-brain barrier (BBB) and efficiently transduce cells of the central nervous system (CNS). However, in the adult CNS, transduction levels by systemically delivered rAAVs are significantly reduced, limiting their potential for CNS gene therapy. Here, we characterized 12 different rAAVEGFPs in the adult mouse CNS following intravenous delivery. We show that the capability of crossing the adult BBB and achieving widespread CNS transduction is a common character of AAV serotypes tested. Of note, rAAVrh.8 is the leading vector for robust global transduction of glial and neuronal cell types in regions of clinical importance such as cortex, caudate-putamen, hippocampus, corpus callosum, and substantia nigra. It also displays reduced peripheral tissue tropism compared to other leading vectors. Additionally, we evaluated rAAVrh.10 with and without microRNA (miRNA)-regulated expressional detargeting from peripheral tissues for systemic gene delivery to the CNS in marmosets. Our results indicate that rAAVrh.8, along with rh.10 and 9, hold the best promise for developing novel therapeutic strategies to treat neurological diseases in the adult patient population. Additionally, systemically delivered rAAVrh.10 can transduce the CNS efficiently, and its transgene expression can be limited in the periphery by endogenous miRNAs in adult marmosets.