Modified cyclodextrin-based nanoparticles mediated delivery of siRNA for huntingtin gene silencing across an in vitro BBB model

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dc.contributor.authorMendonça, Monique C. P.
dc.contributor.authorCronin, Michael F.
dc.contributor.authorCryan, John F.
dc.contributor.authorO'Driscoll, Caitríona M.
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderEuropean Regional Development Funden
dc.date.accessioned2021-12-02T10:51:08Z
dc.date.available2021-12-02T10:51:08Z
dc.date.issued2021-11-15
dc.date.updated2021-12-01T14:17:11Z
dc.description.abstractHuntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene, leading to a toxic version of the HTT protein. There are currently no disease-modifying therapies available. In this scenario, gene-based treatments for HD aimed at lowering HTT levels have become one of the most promising emerging therapeutic options. To date, however, promising results have only been achieved following direct intrathecal or intracranial injections designed to circumvent the blood-brain barrier (BBB). Consequently, efforts to develop less invasive delivery platforms are highly desirable. Here, we described a novel delivery system based on modified cyclodextrin nanoparticles (CDs) loaded with small interfering RNAs (siRNAs) targeting HTT and complexed with the rabies virus glycoprotein (RVG), a BBB-shuttle peptide. Results using an in vitro BBB model, indicate the formulation successfully crosses the brain endothelial cells, releases the encapsulated siRNAs into the cytoplasm of neuronal cells, and mediates downregulation of HTT. In conclusion, the CD platform is a promising option for delivery of siRNA-based therapeutics for HD with wider potential to treat other diseases with a genetically validated target in the central nervous system.en
dc.description.sponsorshipScience Foundation Ireland (SFI) and the European Regional Development Fund (ERDF) (under grant number 13/RC/2073_2 (Centre for Research in Medical Devices, CÚRAM))en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMendonça, M., Cronin, M., Cryan, J. and O'Driscoll, C., (2021) ‘Modified cyclodextrin-based nanoparticles mediated delivery of siRNA for huntingtin gene silencing across an in vitro BBB model’, European Journal of Pharmaceutics and Biopharmaceutics, 169, pp. 309-318. doi: 10.1016/j.ejpb.2021.11.003en
dc.identifier.doi10.1016/j.ejpb.2021.11.003en
dc.identifier.endpage318en
dc.identifier.issn0939-6411
dc.identifier.journaltitleEuropean Journal Of Pharmaceutics And Biopharmaceuticsen
dc.identifier.startpage309en
dc.identifier.urihttps://hdl.handle.net/10468/12299
dc.identifier.volume169en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Research Centres/13/RC/2073/IE/C�RAM - Centre for Research in Medical Devices/en
dc.relation.urihttps://www.sciencedirect.com/science/article/pii/S0939641121002769
dc.rights© 2021 Elsevier B.V. This manuscript version is made available under the CC BY-NC-ND 4.0 license.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectHuntington's diseaseen
dc.subjectNanocarriersen
dc.subjectNon-viral gene therapyen
dc.subjectRVGen
dc.subjectTargeted cyclodextrinsen
dc.titleModified cyclodextrin-based nanoparticles mediated delivery of siRNA for huntingtin gene silencing across an in vitro BBB modelen
dc.typeArticle (peer-reviewed)en
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