Modified cyclodextrins as novel non-viral vectors for neuronal siRNA delivery: focus on Huntington’s disease

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dc.check.embargoformatNot applicableen
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dc.contributor.advisorO'Driscoll, Caitríona M.en
dc.contributor.advisorCryan, John F.en
dc.contributor.authorGodinho, Bruno M. D. C.
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderIrish Drug Delivery Networken
dc.date.accessioned2014-02-24T16:29:43Z
dc.date.available2014-02-24T16:29:43Z
dc.date.issued2014
dc.date.submitted2014
dc.description.abstractHuntington’s Disease (HD) is a rare autosomal dominant neurodegenerative disease caused by the expression of a mutant Huntingtin (muHTT) protein. Therefore, preventing the expression of muHTT by harnessing the specificity of the RNA interference (RNAi) pathway is a key research avenue for developing novel therapies for HD. However, the biggest caveat in the RNAi approach is the delivery of short interfering RNA (siRNAs) to neurons, which are notoriously difficult to transfect. Indeed, despite the great advances in the field of nanotechnology, there remains a great need to develop more effective and less toxic carriers for siRNA delivery to the Central Nervous System (CNS). Thus, the aim of this thesis was to investigate the utility of modified amphiphilic β-cyclodextrins (CDs), oligosaccharide-based molecules, as non-viral vectors for siRNA delivery for HD. Modified CDs were able to bind and complex siRNAs forming nanoparticles capable of delivering siRNAs to ST14A-HTT120Q cells and to human HD fibroblasts, and reducing the expression of the HTT gene in these in vitro models of HD. Moreover, direct administration of CD.siRNA nanoparticles into the R6/2 mouse brain resulted in significant HTT gene expression knockdown and selective alleviation of rotarod motor deficits in this mouse model of HD. In contrast to widely used transfection reagents, CD.siRNA nanoparticles only induced limited cytotoxic and neuroinflammatory responses in multiple brain-derived cell-lines, and also in vivo after single direct injections into the mouse brain. Alternatively, we have also described a PEGylation-based formulation approach to further stabilise CD.siRNA nanoparticles and progress towards a systemic delivery nanosystem. Resulting PEGylated CD.siRNA nanoparticles showed increased stability in physiological saltconditions and, to some extent, reduced protein-induced aggregation. Taken together, the work outlined in this thesis identifies modified CDs as effective, safe and versatile siRNA delivery systems that hold great potential for the treatment of CNS disorders, such as HD.en
dc.description.sponsorshipScience Foundation Ireland (07/SRC/B1154)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationGodinho, B. M. D. C. 2014. Modified cyclodextrins as novel non-viral vectors for neuronal siRNA delivery: focus on Huntington’s disease. PhD Thesis, University College Cork.en
dc.identifier.endpage290
dc.identifier.urihttps://hdl.handle.net/10468/1411
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2014, Bruno M. D. C. Godinhoen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectRNA interferenceen
dc.subjectCNS deliveryen
dc.subjectNeurodegenerationen
dc.subjectGene therapyen
dc.subjectNanotoxicologyen
dc.subjectPEGylationen
dc.subjectNeuroinflammationen
dc.subjectNanotechnologyen
dc.subject.lcshHuntington's chorea--Gene therapyen
dc.subject.lcshDrug delivery systemsen
dc.thesis.opt-outfalse
dc.titleModified cyclodextrins as novel non-viral vectors for neuronal siRNA delivery: focus on Huntington’s diseaseen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
ucc.workflow.supervisorj.cryan@ucc.ie
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