Applications and Challenges of Genome Engineering Technologies in the Treatment of Cystic Fibrosis

Cystic fibrosis is an autosomal recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to CFTR dysfunction and impaired ion transport, which subsequently results in progressive dysfunction of the digestive and respiratory systems and reduced life expectancy. Although current therapies, including airway clearance techniques, antibiotics, pancreatic enzyme replacement therapy, CFTR modulators, and RNA-based approaches, have significantly improved survival and the quality of life, most of these therapies primarily focus on symptom management and are limited by genotype specificity, transient efficacy, and the inability to permanently correct the underlying genetic defect. As a result, patients may require lifelong treatment. Genome engineering technologies appeared as promising causative therapeutic strategies to address cystic fibrosis by directly repairing or replacing defective CFTR alleles. Recently, the latest progress in base editing, prime editing, and gene addition technology has successfully repaired the CFTR function of common and rare mutations in patient-derived airway epithelial cells and organoids, highlighting the potential for long-lasting and mutation-specific repair. However, significant challenges remain, including the effective delivery to airway stem cells and progenitor cells, achieving sufficient in vivo editing efficiency, minimizing the off-target effects, as well as solving ethical, regulatory, and manufacturing barriers. Overall, genome editing provides a potentially transformative method for the treatment of cystic fibrosis, which is expected to achieve long-term disease correction and surpass lifelong symptomatic treatment.