CFTR mRNA-Based Gene Therapy for Cystic Fibrosis: A Mutation-Agnostic Strategy to Restore Ion Transport Function

Abstract: Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the CFTR gene, leading to dysfunctional chloride ion transport across epithelial cells. This results in the accumulation of thick, sticky mucus, primarily affecting the lungs, pancreas, and gastrointestinal tract, leading to chronic respiratory infections and progressive lung damage. Although CFTR modulators have significantly improved outcomes for some patients, their efficacy is limited to specific mutations, leaving many without adequate treatment. CFTR-mRNA-based gene therapy serves as an advantageous therapeutic method for all mutations, independent of the treatment target. Through synthetic CFTR mRNA delivery to epithelial cells using this method, the cells can synthesize the functional CFTR protein required for proper ion transport and mucus hydration. mRNA therapy avoids nuclear entry and genomic integration, reducing the risk of insertional mutagenesis and long-term genetic alterations. Lipid nanoparticles, together with other non-viral delivery carriers, demonstrate significant potential to protect mRNA structures and enhance their ability to enter cells while promoting protein production. Research conducted using animal models has revealed that mRNA therapy leads to the successful restoration of CFTR function, accompanied by improved airway hydration outcomes. Ongoing challenges exist for this therapy, as mRNA encounters instability issues while triggering immune reactions and requires constant dose delivery. Multiple scientific research fields are collaborating on mRNA engineering advancements, along with the development of delivery technologies and combination therapy strategies, to overcome existing obstacles. The study examines current therapeutic approaches while assessing delivery pathways and pharmaceutical advancements, as well as expected research directions regarding CFTR-mRNA therapy, which demonstrates potential to treat all Cystic fibrosis patients through a single, comprehensive treatment.