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

Diana Alarcón-Arís, Rubén Pavia-Collado, Lluis Miquel-Rio, Valentín Coppola-Segovia, Albert Ferrés-Coy, Esther Ruiz-Bronchal, Mireia Galofré, Verónica Paz, Leticia Campa, Raquel Revilla, Andrés Montefeltro, Jeffrey H. Kordower, Miquel Vila, Francesc Artigas, Analia Bortolozzi

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Background: Progressive neuronal death in monoaminergic nuclei and widespread accumulation of α-synuclein are neuropathological hallmarks of Parkinson's disease (PD). Given that α-synuclein may be an early mediator of the pathological cascade that ultimately leads to neurodegeneration, decreased α-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 α-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 α-synuclein overexpression in dopamine neurons prevented the synthesis and accumulation of α-synuclein in the connected brain regions, improving dopamine neurotransmission. Likewise, the four-week IND-ASO treatment led to decreased levels of endogenous α-synuclein protein in the midbrain monoamine nuclei of nonhuman primates, which are affected early in PD. Conclusions: : The inhibition of α-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).

Original languageEnglish (US)
Article number102944
StatePublished - Sep 2020
Externally publishedYes


  • Antisense oligonucleotide
  • Axonal neurodegeneration
  • Dopamine neurotransmission
  • Mouse and monkey models
  • Parkinson's disease
  • α-Synuclein

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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