Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys

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.