Cystic Fibrosis Research Paper

Cystic Fibrosis is an autosomal recessive condition with roughly 1 in 30 Americans being carriers and 30,000 having the disease itself [1]. Its cause, generally speaking, is a mutation with a protein known as Cystic Fibrosis Transmembrane Conductance Regulator (CFTR.) Normally the CFTR protein is folded with the help of chaperone proteins, checked for mutaions by the endoplasmic reticulum and then moved to the apical surface of epithetical cells where it channels chloride ions out of epithelial cells and into mucus membranes [2]. Water then follows the chloride ions via simple osmosis allowing for a “less thick” mucus membrane. CFTR, however, is an immensely complicated protein with many folding steps and 1000s of mutations. The most common mutation is known as ΔF508 (deletion of a phenylalanine at residue 508) which accounts for roughly 70% of mutations worldwide [3]. There are a few other common mutations such as G551D and V232D [2].
Interestingly CFTR rarely makes it to the cell surface even in persons expressing wild-type CFTR. The sheer complexity of the protein causes about 70% of CFTR to be moved to a degradation pathway by the endoplasmic quality control system (ERQC) even in healthy individuals

The drug that acts to correct this mutation, Corr-4a, rescues the protein via two mechanisms [2]. First, small amounts of CFTR-ΔF508 are corrected, allowing some of the protein to be normally inserted into the membrane [2]. In addition, Corr-4a also “tricks” the ERQC into inserting the mutant CFTR-ΔF508 into the membrane where it still functions, albeit not at the same level as the wild-type [2]. In addition to allowing the insertion of the ΔF508 mutant, Corr-4a also allows the insertion of a variety of other CFTR mutations the second one of biggest concern being V232D