CRISPR gene editing for Cystic Fibrosis: targeting the G542X mutation with base editor engineered virus-like particles

Simple item page
dc.check.date2031-05-31
dc.check.infoControlled Access
dc.contributor.advisorHarrison, Patrick
dc.contributor.advisorScallan, Martina
dc.contributor.authorNicosia, Luciaen
dc.date.accessioned2026-01-26T15:19:03Z
dc.date.available2026-01-26T15:19:03Z
dc.date.issued2025
dc.date.submitted2025
dc.descriptionControlled Access
dc.description.abstractCystic Fibrosis (CF) is a severe genetic disorder affecting hundreds of thousands of individuals worldwide. Approximately 10% of CF patients currently lack treatment options beyond symptomatic care and face a reduced life expectancy. CRISPR-based gene editing offers the potential for a cure, by addressing the underlying cause of the disease. The doctoral work presented in this dissertation explored the avenue of CRISPR therapeutic gene editing for CF, while also testing and characterizing a recently emerged delivery technology in the form of virus-like particles. This thesis opens with a systematic review of state-of-the-art CRISPR editing strategies and their application to CF-causing variants, highlighting challenges and gaps that guided the subsequent experimental work. Building on these insights, a base editing approach was developed to target G542X - the most common CF-causing mutation ineligible to modulator therapy - using engineered virus-like particles (eVLPs). This strategy successfully rescued the mutation in patient-derived intestinal organoids, and prompted further investigation into the eVLPs. Two titration assays and a luminescence-based reporter system were established to standardize and monitor particle-mediated transduction. Finally, extending the G542X-editing strategy to CF airway cells revealed previously unreported, non-canonical base editing outcomes specific to eVLP delivery, that are further explored in this dissertation. The review, assays and experimental findings presented and discussed in this thesis aim to advance gene editing for CF. It is hoped this work will encourage and support future research to prioritize editing strategies for modulator-unresponsive variants, incorporating rigorous validation of delivery vehicles in relevant cell types, and integrating transcriptomic, functional and in-vivo studies.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationNicosia, L. 2025. CRISPR gene editing for Cystic Fibrosis: targeting the G542X mutation with base editor engineered virus-like particles. PhD Thesis, University College Cork.
dc.identifier.endpage207
dc.identifier.urihttps://hdl.handle.net/10468/18467
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2025, Lucia Nicosia.
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/
dc.subjectCystic Fibrosis
dc.subjectGene editing
dc.subjectCRISPR
dc.subjectVirus-like particles
dc.titleCRISPR gene editing for Cystic Fibrosis: targeting the G542X mutation with base editor engineered virus-like particles
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
PhD Thesis Lucia Nicosia.pdf
Size:
8.31 MB
Format:
Adobe Portable Document Format
Description:
Full Text E-thesis
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
5.2 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Research Theses
College of Medicine and Health - Doctoral Theses
College of Science, Engineering and Food Science - Doctoral Theses
Microbiology - Doctoral Theses
Physiology - Doctoral Theses