Anti a synuclein ASO delivered to monoamine neurons prevents a synuclein accumulation in a Parkinson's disease like mouse model and in monkeys
Background Progressive neuronal death in monoaminergic nuclei and widespread accumulation of a synuclein are neuropathological hallmarks of Parkinson's disease (PD) Given that a synuclein may be an early mediator of the pathological cascade that ultimately leads to neurodegeneration, decreased a 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 a 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 a synuclein overexpression in dopamine neurons prevented the synthesis and accumulation of a synuclein in the connected brain regions, improving dopamine neurotransmission. Likewise, the four week IND ASO treatment led to decreased levels of endogenous a synuclein protein in the midbrain monoamine nuclei of nonhuman primates, which are affected early in PD. Conclusions The inhibition of a 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. Funding Grants SAF2016 75797 R, RTC 2014 2812 1 and RTC 2015 3309 1, Ministry of Economy and Competitiveness (MINECO) and European Regional Development Fund (ERDF) UE; Grant ID 9238, Michael J. Fox Foundation; and Centres for Networked Biomedical Research on Mental Health (CIBERSAM) and on Neurodegenerative Diseases (CIBERNED)
EBioMedicine