Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems
Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems
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DOI：
10.1038/gt.2011.216
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发表时间：
2013-01-01
期刊：
影响因子：
5.1
通讯作者：
Chan, J. K. Y.
中科院分区：
文献类型：
--
作者：
Mattar, C. N.;Waddington, S. N.;Chan, J. K. Y.
围产期致死性神经遗传性疾病的纠正需要在相对难以接近的CNS内有效转导几种细胞类型。小鼠中的静脉内AAV 9递送实现了神经元细胞类型的发育阶段特异性转导，与出生后受体相比，在产前表现出上级神经元靶向效率。由于非人灵长类动物（NHP）模型的临床相关性，我们研究了AAV 9在子宫内基因治疗（IUGT）后阻断NHP CNS的能力。我们通过脐静脉的肝内延续以0.9 G向两个猕猴胎儿注射1 × 10（13）vg scAAV 9-CMV-eGFP。在整个CNS的大多数神经元（包括巢蛋白阳性细胞）、运动神经元和少突胶质细胞中观察到稳健的绿色荧光蛋白（GFP）表达长达14周，星形胶质细胞中的转导率显著较低。还转导了网状和神经节视网膜层中的光感受器和神经元细胞体。在周围神经系统（PNS）中，观察到广泛的神经元转导。在14周收获的组织显示出显著较低的载体拷贝数和GFP水平，尽管GFP表达细胞的百分比保持稳定。因此，妊娠晚期的AAV 9-IUGT有效地转导具有神经元偏好的CNS和PNS两者，其与以神经病理学的围产期发作为特征的遗传性病症具有翻译相关性。Gene Therapy（2013）20，69-83; doi：10.1038/gt.2011.216; 2012年1月26日在线发表
Correction of perinatally lethal neurogenetic diseases requires efficient transduction of several cell types within the relatively inaccessible CNS. Intravenous AAV9 delivery in mouse has achieved development stage-specific transduction of neuronal cell types, with superior neuron-targeting efficiency demonstrated in prenatal compared with postnatal recipients. Because of the clinical relevance of the non-human primate (NHP) model, we investigated the ability of AAV9 to transduce the NHP CNS following intrauterine gene therapy (IUGT). We injected two macaque fetuses at 0.9 G with 1 x 10(13) vg scAAV9-CMV-eGFP through the intrahepatic continuation of the umbilical vein. Robust green fluorescent protein (GFP) expression was observed for up to 14 weeks in the majority of neurons (including nestin-positive cells), motor neurons and oligodendrocytes throughout the CNS, with a significantly lower rate of transduction in astrocytes. Photoreceptors and neuronal cell bodies in the plexiform and ganglionic retinal layers were also transduced. In the peripheral nervous system (PNS), widespread transduction of neurons was observed. Tissues harvested at 14 weeks showed substantially lower vector copy number and GFP levels, although the percentage of GFP-expressing cells remained stable. Thus, AAV9-IUGT in late gestation efficiently transduces both the CNS and PNS with neuronal predilection, of translational relevance to hereditary disorders characterized by perinatal onset of neuropathology. Gene Therapy (2013) 20, 69-83; doi:10.1038/gt.2011.216; published online 26 January 2012