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

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dc.contributor.advisor O'Driscoll, Caitríona M. en
dc.contributor.advisor Cryan, John F. en Godinho, Bruno M. D. C. 2014-02-24T16:29:43Z 2014-02-24T16:29:43Z 2014 2014
dc.identifier.citation Godinho, 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.endpage 290
dc.description.abstract Huntington’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.sponsorship Science Foundation Ireland (07/SRC/B1154) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2014, Bruno M. D. C. Godinho en
dc.rights.uri en
dc.subject RNA interference en
dc.subject CNS delivery en
dc.subject Neurodegeneration en
dc.subject Gene therapy en
dc.subject Nanotoxicology en
dc.subject PEGylation en
dc.subject Neuroinflammation en
dc.subject Nanotechnology en
dc.subject.lcsh Huntington's chorea--Gene therapy en
dc.subject.lcsh Drug delivery systems en
dc.title Modified cyclodextrins as novel non-viral vectors for neuronal siRNA delivery: focus on Huntington’s disease en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text available en No embargo required en
dc.description.version Accepted Version
dc.contributor.funder Science Foundation Ireland en
dc.contributor.funder Irish Drug Delivery Network en
dc.description.status Not peer reviewed en Pharmacy en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
dc.internal.conferring Spring Conferring 2014 en

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© 2014, Bruno M. D. C. Godinho Except where otherwise noted, this item's license is described as © 2014, Bruno M. D. C. Godinho
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