TY - JOUR
T1 - Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys
AU - Alarcón-Arís, Diana
AU - Pavia-Collado, Rubén
AU - Miquel-Rio, Lluis
AU - Coppola-Segovia, Valentín
AU - Ferrés-Coy, Albert
AU - Ruiz-Bronchal, Esther
AU - Galofré, Mireia
AU - Paz, Verónica
AU - Campa, Leticia
AU - Revilla, Raquel
AU - Montefeltro, Andrés
AU - Kordower, Jeffrey H.
AU - Vila, Miquel
AU - Artigas, Francesc
AU - Bortolozzi, Analia
N1 - Funding Information:
Funding sources: SAF2016-75797-R, Retos-Colaboración Subprogram RTC-2014-2812-1 and RTC-2015-3309-1, Ministry of Economy and Competitiveness (MINECO) and European Regional Development Fund (ERDF), UE; Therapeutic Pipeline Program Spring 2014 Program, grant ID: 9238, The Michael J. Fox Foundation; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED). Role of the funding sources: generation and characterization of a PD-like mouse model, studies in monkeys, studies of the efficacy of a new PD therapy based on an indatraline-conjugated antisense oligonucleotide. Funding sources were not involved in writing, compiling, analysing, interpreting, or presenting the study, and full access to study data was provided.
Funding Information:
This study was supported by grants SAF2016-75797-R, Retos-Colaboración Subprogram RTC-2014-2812-1 and RTC-2015-3309-1 , Ministry of Economy and Competitiveness (MINECO) and European Regional Development Fund (ERDF), UE; Therapeutic Pipeline Program Spring 2014 Program , grant ID: 9238 , The Michael J. Fox Foundation; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED).
Funding Information:
We thank M. Calvo and E. Coll for outstanding technical support in the confocal microscopy unit (CCiT-UB). We thank to the Coordena??o de Aperfei??amento de Nivel Superior (CAPES- PDSE: 19/2016 88881.135527/2016-01), Brazil, for their financial scholarship support to V.C-S. We would also like to thank Prof. Silvio Zanata for his valuable comments of the significance of results. This study was supported by grants SAF2016-75797-R, Retos-Colaboraci?n Subprogram RTC-2014-2812-1 and RTC-2015-3309-1, Ministry of Economy and Competitiveness (MINECO) and European Regional Development Fund (ERDF), UE; Therapeutic Pipeline Program Spring 2014 Program, grant ID: 9238, The Michael J. Fox Foundation; Centro de Investigaci?n Biom?dica en Red de Salud Mental (CIBERSAM), and Centro de Investigaci?n Biom?dica en Red de Enfermedades Neurodegenerativas (CIBERNED). R. Revilla, A. Montefeltro, F. Artigas, M. Vila, and A. Bortolozzi are authors of the patent WO/2011/131693 issued for the siRNA and ASO molecules and the targeting approach related to this work. R. Revilla is board members of nLife Therapeutics S.L. A. Montefeltro is stockholder of nLife Therapeutics S.L. The rest of authors declare no competing interests. Conceptualization, A.B.; methodology R.R. A.M. J.H.K. M.V. and A.B.; investigation, D.A-A. R.P-C. V.C-S. L.M-R. A.F-C. E.R-B. M.G. V.P, L.C. R.R. A.M. J.H.K. M.V. F.A. and A.B; writing, A.B.; revisions, D.A-A. R.P-C. V.C-S. L.M-R. A.F-C. E.R-B. M.G. V.P, L.C. R.R. A.M. J.H.K. M.V. F.A. and A.B; visualization, A.B; supervision, A.B. and funding acquisition, F.A. M.V. and A.B. Supplementary material includes statistical information, toxicity studies in mice and six figures.
Publisher Copyright:
© 2020 The Authors
PY - 2020/9
Y1 - 2020/9
N2 - 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).
AB - 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).
KW - Antisense oligonucleotide
KW - Axonal neurodegeneration
KW - Dopamine neurotransmission
KW - Mouse and monkey models
KW - Parkinson's disease
KW - α-Synuclein
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UR - http://www.scopus.com/inward/citedby.url?scp=85089392159&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2020.102944
DO - 10.1016/j.ebiom.2020.102944
M3 - Article
C2 - 32810825
AN - SCOPUS:85089392159
VL - 59
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
M1 - 102944
ER -