Recombinant Human CFTR protein

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a chloride channel critical for maintaining fluid and electrolyte balance across epithelial surfaces. Dysfunctional CFTR causes cystic fibrosis (CF), a life-limiting genetic disorder affecting multiple organs, particularly the lungs and pancreas. The CFTR gene, identified in 1989. encodes a 1.480-amino-acid protein with two membrane-spanning domains, two nucleotide-binding domains (NBDs), and a regulatory (R) domain. Over 2.000 CFTR mutations have been documented, with F508del (a deletion of phenylalanine at position 508) being the most common, causing misfolding and impaired trafficking to the cell membrane.

Recombinant CFTR protein production emerged as a key strategy for studying CF pathophysiology and developing therapies. Using heterologous expression systems (e.g., mammalian cells, insect cells, or yeast), researchers produce purified CFTR to analyze its structure, function, and interactions with modulators. Structural studies, notably cryo-EM advancements since 2017. have revealed atomic-level details of CFTR gating mechanisms and drug-binding sites, informing precision drug design.

Therapeutics like CFTR modulators (e.g., ivacaftor, lumacaftor, elexacaftor) aim to rescue mutant CFTR function. These drugs were developed using recombinant protein platforms to screen compounds that enhance folding, trafficking, or channel activity. The 2019 FDA-approved Triple Therapy (Trikafta®), combining three modulators, marked a breakthrough, improving lung function in ~90% of CF patients with F508del or similar mutations.

Current research focuses on expanding modulator efficacy to rare mutations, optimizing protein correction strategies, and addressing limitations like high costs and variable patient responses. Recombinant CFTR technology remains central to personalized medicine approaches and gene-editing therapies (e.g., CRISPR-Cas9), aiming for durable CFTR restoration.