AAV-PHP.B Administration Results in a Differential Pattern of CNS Biodistribution in Non-human Primates Compared with Mice
AAV-PHP.B Administration Results in a Differential Pattern of CNS Biodistribution in Non-human Primates Compared with Mice
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DOI：
10.1016/j.ymthe.2019.07.017
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发表时间：
2019-11-06
影响因子：
12.4
通讯作者：
McBride, Jodi L.
中科院分区：
文献类型：
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作者：
Liguore, William A.;Domire, Jacqueline S.;McBride, Jodi L.
重组腺相关病毒（AAV）将转基因递送至CNS的能力已经允许在基因疗法领域中的若干进步以治疗脑部疾病。尽管大多数AAV在外周给药后不容易穿过血脑屏障并进入CNS，但最近已经显示，在注射到眶后窦后，AAV-PHP.B与其亲本血清型AAV 9相比以更高的效率进入小鼠的脑。在此，我们通过比较野生型C57 BL/6 J小鼠中的AAV-PHP.B转导效率扩展了这一基础工作，所述野生型C57 BL/6 J小鼠使用四种临床上适用的递送策略，包括两种血管内（颈静脉内和颈动脉内）和两种脑脊髓液（CSF）内途径（小脑延髓池内和侧脑室内）。我们在更大的动物模型中放大这些比较，并评估AAV-PHP.B在恒河猴中的转导效率。我们发现广泛的和基本相同的中枢神经系统转导小鼠后，所有四种注射策略，而我们观察到的猕猴与广泛的皮质和脊髓转导鞘内给药后，只有非常低的转导后血管内给药的不同模式的转导。总之，这些结果表明，AAV-PHP.B可能是一个有用的基因治疗载体的神经系统疾病，特别是那些源于广泛的皮质或脊髓神经病理学。
The ability of recombinant adeno-associated virus (AAV) to deliver transgenes to the CNS has allowed for several advancements in the field of gene therapy to treat brain disorders. Although most AAVs do not readily cross the blood-brain barrier and transduce the CNS following peripheral administration, AAV-PHP.B has recently been shown to transduce brains of mice with higher efficiency compared with its parent serotype, AAV9, following injection into the retro-orbital sinus. Here, we extended this foundational work by comparing AAV-PHP.B transduction efficiency in wild-type C57BL/6J mice using four clinically applicable delivery strategies including two intravascular (intra-jugular vein and intra-carotid artery) and two intra-cerebral spinal fluid (CSF) routes (intra-cisterna magna and intra-lateral ventricle). We scaled up these comparisons in a larger-animal model and evaluated transduction efficiency of AAV-PHP.B in the rhesus macaque. We found widespread and largely equal CNS transduction in mice following all four injection strategies, whereas we observed a differential pattern of transduction in macaques with broad cortical and spinal cord transduction seen after intrathecal administration and only very low transduction following intravascular administration. Taken together, these results suggest that AAV-PHP.B may be a useful gene therapy vector for neurological disorders, particularly those stemming from broad cortical or spinal cord neuropathology.