Biodistribution of adeno-associated virus type-2 in nonhuman primates after convection-enhanced delivery to brain
Biodistribution of adeno-associated virus type-2 in nonhuman primates after convection-enhanced delivery to brain
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DOI：
10.1038/mt.2008.111
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发表时间：
2008-07-01
影响因子：
12.4
通讯作者：
Bankiewicz, Krystof S.
中科院分区：
文献类型：
--
作者：
Cunningham, Janet;Pivirotto, Philip;Bankiewicz, Krystof S.
AAV 2-hAADC与口服左旋多巴的组合治疗是正在开发用于晚期帕金森病的新型治疗方法。在壳核内输注后6个月，在12只患有帕金森综合征的猴子中，在宽范围的载体剂量下评估AAV 2-hAADC的生物分布。来自大脑所有主要神经解剖区域的定量PCR（Q-PCR）表明载体DNA呈剂量依赖性增加，在靶部位和其他基底神经节组织中检测到99%。在这些组织中，壳核（PT）和苍白球之间的分布差异很大，这是由于载体运输的差异。Q-PCR和免疫细胞化学与先前报道的转基因表达的各种措施，包括芳香族L-氨基酸脱羧酶（AADC）活性测定，行为反应，并在体内成像与正电子发射断层扫描（PET）的结果一致。在脑外，在两个最高剂量组动物的脾脏中检测到痕量载体DNA，但在任何其他外周组织、血液或脑脊液中未检测到。在接受高剂量AAV 2-hAADC或对照AAV 2-GFP的猴中观察到针对2型腺相关病毒（AAV 2）衣壳蛋白的中和抗体滴度的一些增加。该研究进一步验证了对流增强递送（CED）作为病毒载体递送至脑的优选方法，并支持AAV 2-hAADC在患有帕金森病的人中的I期临床测试。
A combination treatment of AAV2-hAADC with oral levodopa is a novel therapeutic approach that is being developed for late-stage Parkinson's disease. Biodistribution of AAV2-hAADC was assessed over a wide range of vector dose in 12 monkeys with parkinsonian syndrome, 6 months after intraputamenal infusion. Quantitative PCR (Q-PCR) from all the major neuroanatomical regions of the brain indicated a dose-dependent increase in vector DNA, with 99% being detected in the target site and other basal ganglia tissues. Within these tissues, the distribution varied widely between the putamen (PT) and the globus pallidus, and this was attributed to differences in vector transport. Q-PCR and immunocytochemistry were consistent with results reported earlier for various measures of transgene expression including aromatic L-amino acid decarboxylase (AADC) activity assays, behavioral response, and in vivo imaging with positron emission tomography (PET). Outside of the brain, trace amounts of vector DNA were detected in the spleens of animals in the two highest dose groups, but not in any other peripheral tissue, blood, or cerebrospinal fluid. Some increase in neutralizing antibody titers to adeno-associated virus type-2 (AAV2) capsid protein was observed in monkeys that received high doses of AAV2-hAADC or control AAV2-GFP. This study further validates convection-enhanced delivery (CED) as the preferred method of viral vector delivery to the brain, and supports a Phase I clinical testing of AAV2-hAADC in humans with Parkinson's disease.