Cystic fibrosis transmembrane conductance regulator mRNA and translation machinery (CFTR mRNA)

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mRNA and the cellular translation machinery represent a specialized therapeutic axis for treating Cystic Fibrosis (CF), particularly for patients with Class I nonsense mutations (NIH, 2019). CFTR is a cAMP-regulated chloride channel essential for maintaining epithelial fluid homeostasis; mutations in the CFTR gene lead to defective ion transport and the accumulation of thick mucus in the lungs and other organs (MedlinePlus, 2008). In patients with nonsense mutations, premature stop codons in the CFTR mRNA result in truncated, non-functional proteins and reduced transcript levels due to nonsense-mediated decay (NMD) (Frontiers in Pharmacology, 2023). Drugs targeting this machinery include read-through agents like ataluren and ELX-02, which bind to the ribosome to facilitate the incorporation of near-cognate tRNAs at premature stop sites, thereby restoring full-length protein synthesis (Eloxx Pharmaceuticals, 2020; NIH, 2020). Additionally, mRNA replacement therapies like MRT5005 deliver exogenous, functional CFTR mRNA to bypass the genetic defect entirely, while amplifiers like nesolicaftor increase the stability and availability of the mRNA transcript (Cystic Fibrosis Foundation, 2023; Frontiers in Pharmacology, 2023). Despite their potential as mutation-agnostic or nonsense-specific treatments, these approaches face challenges such as efficient delivery to the airway epithelium and potential toxicities like nephrotoxicity or immune-mediated febrile reactions (NIH, 2019; MaineHealth, 2023).

Other names

CFTR transcriptCFTR messenger RNACFTR mRNA-ribosome complexCFTR translation axis

Translational read-through of premature termination codons (PTCs) (Eloxx Pharmaceuticals, 2020), mRNA replacement therapy (Cystic Fibrosis Foundation, 2023), mRNA amplification (Frontiers in Pharmacology, 2023), and inhibition of nonsense-mediated mRNA decay (NMD) (NIH, 2015).