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首页> 外文期刊>Human gene therapy. Clinical development >Direct and Retrograde Transduction of Nigral Neurons with AAV6, 8, and 9 and Intraneuronal Persistence of Viral Particles
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Direct and Retrograde Transduction of Nigral Neurons with AAV6, 8, and 9 and Intraneuronal Persistence of Viral Particles

机译：AAV6、8和9对黑质神经元的直接和逆行转导以及病毒颗粒的神经内持久性

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摘要

Recombinant adeno-associated viral (AAV) vectors of serotypes 6, 8, and 9 were characterized as tools for gene delivery to dopaminergic neurons in the substantia nigra for future gene therapeutic applications in Parkinson's disease. While vectors of all three serotypes transduced nigral dopaminergic neurons with equal efficiency when directly injected to the substantia nigra, AAV6 was clearly superior to AAV8 and AAV9 for retrograde transduction of nigral neurons after striatal delivery. For sequential transduction of nigral dopaminergic neurons, the combination of AAV9 with AAV6 proved to be more powerful than AAV8 with AAV6 or repeated AAV6 administration. Surprisingly, single-stranded viral genomes persisted in nigral dopaminergic neurons within cell bodies and axon terminals in the striatum, and intact assembled AAV capsid was enriched in nuclei of nigral neurons, 4 weeks after virus injections to the substantia nigra. 6-Hydroxydopamine (6-OHDA)-induced degeneration of dopaminergic neurons in the substantia nigra reduced the number of viral genomes in the striatum, in line with viral genome persistence in axon terminals. However, 6-OHDA-induced axonal degeneration did not induce any transsynaptic spread of AAV infection in the striatum. Therefore, the potential presence of viral particles in axons may not represent an important safety issue for AAV gene therapy applications in neurodegenerative diseases.
机译：血清型6、8和9的重组腺相关病毒（AAV）载体被表征为用于将基因传递至黑质中多巴胺能神经元的工具，用于将来在帕金森氏病中的基因治疗应用。当所有三种血清型的载体直接注射到黑质中时均能以相同的效率转导黑质多巴胺能神经元，而对于纹状体分娩后的黑质神经元逆行转导，AAV6明显优于AAV8和AAV9。对于黑质多巴胺能神经元的顺序转导，AAV9和AAV6的结合被证明比AAV8和AAV6或重复给药更有效。令人惊讶的是，病毒注射到黑质后4周，单链病毒基因组在细胞体和纹状体中轴突末端的黑色多巴胺能神经元中持续存在，而完整组装的AAV衣壳富含黑色神经元核。 6-羟基多巴胺（6-OHDA）诱导的黑质多巴胺能神经元变性减少了纹状体中病毒基因组的数量，这与轴突末端的病毒基因组持久性相符。但是，6-OHDA引起的轴突变性并没有引起纹状体中AAV感染的任何突触传播。因此，轴突中病毒颗粒的潜在存在可能并不代表AAV基因治疗在神经退行性疾病中的重要安全问题。

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