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RNA interference therapy for Machado-Joseph disease: Long-term safety profile of lentiviral vectors encoding short hairpin RNAs targeting mutant ataxin-3

2019-07Journal article Restricted access
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dc.contributor.authorNóbrega, Clévio
dc.contributor.authorCodesso, Jose Miguel
dc.contributor.authorMendonca, Liliana
dc.contributor.authorde Almeida, Luis Pereira
dc.date.accessioned2020-07-24T10:52:16Z
dc.date.available2020-07-24T10:52:16Z
dc.date.issued2019-07
dc.description.abstractMachado-Joseph disease (MJD) or spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by an abnormal repetition of a CAG codon in the MJD1 gene. This expansion translates into a long polyglutamine tract, leading to the misfolding of the mutant protein ataxin-3, which abnormally accumulates in the nucleus, thus leading to neurodegeneration in specific brain regions. No treatment able to modify the progression of the disease is available. However, it has previously been shown that specific silencing of mutant ataxin-3 by RNA interference with viral vectors is a promising therapeutic strategy for MJD. Nevertheless, reports of cytotoxic effects of this technology led to the safety profile of the previously tested lentiviral vectors encoding short hairpin (sh)RNAs (LV-shmutatx3) targeting mutant ataxin-3 upon brain injection being investigated. For this purpose, the vectors were injected in the mouse striata, and neuronal dysfunction, degeneration, gliosis, off-target effects, and saturation of the RNA interference machinery were evaluated. It was found that: (1) LV-shmutatx3 mediated stable and long-term expression of the shRNA in neurons of the mouse striatum; (2) neuronal dysfunction evaluated by darpp-32, NeuN, and cresyl violet staining, initially more pronounced, became indistinguishable from the phosphate-buffered saline group at 8 weeks and resolved within 20 weeks; (3) astrocytic activation was present, which resolved within 8 weeks; (4) microglial activity and proinflammatory cytokines release were present, which resolved and normalized within 20 weeks; and (5) there were no off-target effects or saturation of the endogenous RNA interference processing machinery in the mouse striatum. The data show that injection of lentiviral vectors encoding a shRNA targeting mutant ataxin-3 in the mouse brain induce transient dysfunctions, which resolve within 20 weeks. Importantly, long-term expression (up to 20 weeks post injection) of this shRNA (driven by H1 promoter) led to no toxic effect in vivo. This study thus constitutes an additional step in a future translation of gene silencing as a therapy for MJD.
dc.description.sponsorshipEuropean Regional Development Fund (ERDF), through the CENTRO 2020 Regional Operational ProgrammeEuropean Union (EU) [CENTRO-01-0145-FEDER-000008: BrainHealth 2020]
dc.description.sponsorshipEuropean Regional Development Fund (ERDF), through COMPETE 2020Operational Programme for Competitiveness and InternationalizationEuropean Union (EU)
dc.description.sponsorshipFCT-Fundacao para a Ciencia e a Tecnologia, I.P. [POCI-01-0145-FEDER-016719 (PTDC/NEU-NMC/0084/2014), POCI-01-0145FEDER-007440 (UID/NEU/04539/2013), POCI-01-0145-FEDER-016390: CANCEL STEM]
dc.description.sponsorshipCENTRO 2020
dc.description.sponsorshipFCTPortuguese Foundation for Science and Technology [CENTRO-01-0145-FEDER-022095: ViraVector]
dc.description.sponsorshipproject ESMI under the EU Joint Program-Neurodegenerative Disease Research (JPND) [JPCOFUND/0001/2015]
dc.description.sponsorshipproject ModelPolyQ under the EU Joint Program-Neurodegenerative Disease Research (JPND) [JPCOFUND/0005/2015]
dc.description.sponsorshipEuropean Union H2020 program [643417]
dc.description.sponsorshipFCTPortuguese Foundation for Science and Technology
dc.description.sponsorshipFrench Muscular Dystrophy AssociationAssociation Francaise contre les Myopathies
dc.description.sponsorshipNational Ataxia Foundation
dc.description.sponsorshipRichard Chin and Lily Lock Machado Joseph Disease Research Fund
dc.description.sponsorshipAmerican Portuguese Biomedical Research Fund
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1089/hum.2018.157
dc.identifier.issn1043-0342
dc.identifier.issn1557-7422
dc.identifier.urihttp://hdl.handle.net/10400.1/14340
dc.language.isoeng
dc.peerreviewedyes
dc.publisherMary Ann Liebert, Inc
dc.subjectSpinocerebellar ataxia
dc.subjectForebrain neurogenesis
dc.subjectImproves motor
dc.subjectRat model
dc.subjectBrain
dc.subjectOverexpression
dc.subjectNeuropathology
dc.subjectReplacement
dc.subjectHuntingtin
dc.subjectMicroglia
dc.titleRNA interference therapy for Machado-Joseph disease: Long-term safety profile of lentiviral vectors encoding short hairpin RNAs targeting mutant ataxin-3
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage854
oaire.citation.issue7
oaire.citation.startPage841
oaire.citation.titleHuman Gene Therapy
oaire.citation.volume30
person.familyNameNóbrega
person.givenNameClévio
person.identifier.ciencia-idC510-7F41-BAF8
person.identifier.orcid0000-0002-8312-5292
person.identifier.ridM-6047-2013
person.identifier.scopus-author-id24473454000
rcaap.rightsrestrictedAccess
rcaap.typearticle
relation.isAuthorOfPublication725ea6f8-1363-4cee-9cf2-5ac7303b3ba9
relation.isAuthorOfPublication.latestForDiscovery725ea6f8-1363-4cee-9cf2-5ac7303b3ba9

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