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 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, decrease...
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Language: | English |
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Elsevier
2020-09-01
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Series: | EBioMedicine |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396420303200 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys EBioMedicine α-Synuclein Antisense oligonucleotide Axonal neurodegeneration Dopamine neurotransmission Mouse and monkey models Parkinson's disease |
author_facet |
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 |
author_sort |
Diana Alarcón-Arís |
title |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
title_short |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
title_full |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
title_fullStr |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
title_full_unstemmed |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
title_sort |
anti-α-synuclein aso delivered to monoamine neurons prevents α-synuclein accumulation in a parkinson's disease-like mouse model and in monkeys |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2020-09-01 |
description |
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). |
topic |
α-Synuclein Antisense oligonucleotide Axonal neurodegeneration Dopamine neurotransmission Mouse and monkey models Parkinson's disease |
url |
http://www.sciencedirect.com/science/article/pii/S2352396420303200 |
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doaj-f7a8a6890d914666847af3b3276a164a2020-11-25T03:36:29ZengElsevierEBioMedicine2352-39642020-09-0159102944Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeysDiana Alarcón-Arís0Rubén Pavia-Collado1Lluis Miquel-Rio2Valentín Coppola-Segovia3Albert Ferrés-Coy4Esther Ruiz-Bronchal5Mireia Galofré6Verónica Paz7Leticia Campa8Raquel Revilla9Andrés Montefeltro10Jeffrey H. Kordower11Miquel Vila12Francesc Artigas13Analia Bortolozzi14Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, SpainInstitut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Laboratory of Neurobiology and Redox Pathology, Department of Basic Pathology, Federal University of Paraná (UFPR), Curitiba, BrazilInstitut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, SpainInstitut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, SpainInstitut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, SpainInstitut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, SpainInstitut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spainn-Life Therapeutics, S.L., Granada, Spainn-Life Therapeutics, S.L., Granada, SpainDepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL, USANeurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, SpainInstitut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, SpainInstitut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; Corresponding author.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).http://www.sciencedirect.com/science/article/pii/S2352396420303200α-SynucleinAntisense oligonucleotideAxonal neurodegenerationDopamine neurotransmissionMouse and monkey modelsParkinson's disease |