Advisor(s)
Rowe Steven M
Committee Member(s)
Campos-Gomez Javier
Raju S Vamsee
Vijaykumar Kadambari
School
Joint Health Sciences (Interdisciplinary)
Document Type
Thesis
Department (new version)
Joint Health Sciences
Date of Award
9-11-2025
Abstract
Cystic fibrosis (CF) is a life-threatening genetic disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, resulting in impaired chloride ion transport and thickened airway mucus. While CFTR modulators, such as elexacaftor/tezacaftor/ivacaftor (ETI), have improved outcomes for most CF patients, approximately 10% harbor mutations that are unresponsive to these therapies, necessitating alternative treatments. mRNA-based therapies have emerged as promising approaches by directly restoring CFTR protein expression. LUNAR-CFTR, a first-generation CFTR-mRNA lipid nanoparticle (LNP) therapy, has demonstrated partial functional restoration in vitro and vivo models; however, it requires high doses, which limits its clinical utility. This study aims to develop second-generation CFTR-mRNA LNP formulations (CF2.0) designed to produce hyperfunctional CFTR channels, thereby enhancing chloride transport efficiency while reducing dosage requirements. The primary objectives of this study are to (1) quantify CF2.0-induced CFTR protein expression and function in human bronchial epithelial cells, and (2) evaluate CF2.0-mediated improvements in mucociliary clearance (MCC). By optimizing CFTR function per delivered mRNA dose, CF2.0 formulations have the potential to overcome current therapeutic limitations and expand treatment options for patients with refractory CFTR mutations, ultimately restoring the mucociliary clearance. The findings from this study will contribute to the advancement of CFTR-mRNA therapies, providing a novel strategy to enhance clinical outcomes in patients with CF who currently lack effective treatment options.
ProQuest ID
Recommended Citation
Chen, Han-Chung, "Next‑Generation Cftr Mrna Lipid Nanoparticles Confer Supra-Physiological Chloride Currents In Human Airway Epithelial Cells" (2025). All ETDs from UAB. 7417.
https://digitalcommons.library.uab.edu/etd-collection/7417
