Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys
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DOI：
10.1016/j.ebiom.2020.102944
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发表时间：
2020-09-01
期刊：
影响因子：
11.1
通讯作者：
Bortolozzi, Analia
中科院分区：
文献类型：
--
作者：
Alarcon-Aris, Diana;Pavia-Collado, Ruben;Bortolozzi, Analia
背景：单胺能核中的进行性神经元死亡和α-突触核蛋白的广泛积累是帕金森病（PD）的神经病理学标志。鉴于 α-突触核蛋白可能是最终导致神经退行性病变的病理级联反应的早期介质，如果将 α-突触核蛋白合成减少传递到关键受影响的神经元，将减轻神经毒性。方法：我们使用基于新的吲达曲林缀合反义寡核苷酸 (IND-ASO) 的非病毒基因疗法来 在 PD 样小鼠模型和老年非人灵长类动物的单胺神经元中选择性破坏 α-突触核蛋白 mRNA 转录。进行了分子、细胞生物学、组织学、神经化学和行为分析。结果：在 AAV 介导的野生型人 α-突触核蛋白在多巴胺神经元中过度表达的小鼠模型中，脑室内和鼻内 IND-ASO 给药四个星期，可阻止相连大脑区域中 α-突触核蛋白的合成和积累，改善 多巴胺神经传递。同样，为期 4 周的 IND-ASO 治疗导致非人灵长类动物中脑单胺核中内源性 α-突触核蛋白水平下降，这在 PD 早期受到影响。 多巴胺功能，显示反义寡核苷酸作为帕金森病和相关突触核蛋白病的疾病修饰疗法的高翻译价值。 (C) 2020 作者。由 Elsevier B.V. 出版
Background: Progressive neuronal death in monoaminergic nuclei and widespread accumulation of alpha-synuclein are neuropathological hallmarks of Parkinson's disease (PD). Given that alpha-synuclein may be an early mediator of the pathological cascade that ultimately leads to neurodegeneration, decreased alpha-synuclein synthesis will abate neurotoxicity if delivered to the key affected neurons.Methods: We used a non-viral gene therapy based on a new indatraline-conjugated antisense oligonucleotide (IND-ASO) to disrupt the alpha-synuclein mRNA transcription selectively in monoamine neurons of a PD-like mouse model and elderly nonhuman primates. Molecular, cell biology, histological, neurochemical and behavioral assays were performed.Findings: Intracerebroventricular and intranasal IND-ASO administration for four weeks in a mouse model with AAV-mediated wild-type human alpha-synuclein overexpression in dopamine neurons prevented the synthesis and accumulation of alpha-synuclein in the connected brain regions, improving dopamine neurotransmission. Likewise, the four-week IND-ASO treatment led to decreased levels of endogenous alpha-synuclein protein in the midbrain monoamine nuclei of nonhuman primates, which are affected early in PD.Conclusions:: The inhibition of alpha-synuclein production in dopamine neurons and its accumulation in cortical/ striatal projection areas may alleviate the early deficits of dopamine function, showing the high translational value of antisense oligonucleotides as a disease modifying therapy for PD and related synucleinopathies. (C) 2020 The Authors. Published by Elsevier B.V.