huCFTR-G551D Mouse

The cystic fibrosis transmembrane conductance regulator (CFTR) is a critical protein that maintains the salt and water balance across various human organs, including the lungs, pancreas, and sweat glands. The primary function of CFTR is to act as a chloride channel, regulating the transport of chloride and bicarbonate ions across epithelial cell membranes, thereby maintaining tissue fluid balance and pH. This process is ATP-dependent and also modulates the activity of other ion channels and transport proteins ^[1-2]. Mutations in the CFTR gene can lead to chloride channel dysfunction, resulting in various diseases, with cystic fibrosis (CF) being the most common. CF is the most prevalent lethal genetic disease among Caucasians, with an incidence of approximately 1/2,500 to 1/1,800, and about 90,000 cases globally ^[3-4]. The disease is characterized by thickened mucus in the lungs, frequent respiratory infections, pancreatic insufficiency, and male infertility, typically due to vas deferens obstruction. The G551D mutation is a clinically significant genetic defect in the CFTR gene, which is classified as a Class III mutation and is the third most common CF-associated mutation worldwide, occurring in about 3% of CF patients ^[5]. This missense mutation involves a single amino acid substitution where Glycine (G) is replaced by Aspartic Acid (D) at position 551 within the first Nucleotide Binding Domain (NBD1) of the CFTR protein. The defining molecular pathology is a severe gating defect; while the CFTR chloride channel is correctly processed and successfully trafficked to the apical membrane of epithelial cells, its probability of opening is drastically reduced (approximately 100-fold lower than the wild-type channel). This impairment in channel opening results in a critical reduction in chloride and bicarbonate transport, leading to the characteristic buildup of thick, dehydrated mucus in multiple organs and a severe clinical phenotype. Current treatments for CF mainly focus on CFTR modulators to restore the function of the mutated CFTR protein. CFTR modulators are classified into potentiators (which enhance CFTR function) and correctors (which assist in the proper folding and trafficking of CFTR to the cell membrane). Representative drugs include Ivacaftor, Lumacaftor, and triple-combination CFTR modulating therapy Elexacaftor-Tezacaftor-Ivacaftor ^[6]. The G551D mutation holds particular importance in CF research and therapy as it was the first genotype-specific mutation to be successfully targeted by a CFTR potentiator drug, Ivacaftor, which functions by increasing the opening probability of the mutant channel.

huCFTR-G551D mice were developed by introducing the G551D mutation into the CFTR-humanized mouse model (Catalog Number: C001964), creating a humanized disease model. It is suitable for research into CF mechanisms and the development of therapies targeting the CFTR G551D mutation. This strain requires feeding with intestinal cleansers to maintain survival. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation models based on the CFTR-humanized strain and provide customized services for specific mutations to meet the experimental needs in pharmacology and other fields.