Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The gene encodes for the CFTR protein, which is transported to the cell membrane where it functions as a channel for the transport of salt and water across the cell.
Defects in this protein can result in improper salt and water balance, and the secretion of a sticky and thick mucus instead of normal watery mucus.
While there are nearly 2,000 mutations that can cause CF, the most common mutation — seen in about 90 percent of the affected population — is the deletion of the amino acid phenylalanine at position 508 (F508del) in the CFTR protein. F508del can result in the improper folding of the CFTR protein, thereby preventing its transport to the cell membrane.
What are CFTR correctors?
In CF patients with the F508del mutation, the faulty CFTR protein is not able to move to the cell membrane due to its incorrect folding and hence gets degraded by the cell. CFTR correctors, a category of CFTR modulators, aim to rectify this defect so that the protein can be transported to cell membranes without being degraded despite the mutation still being present in the gene.
CFTR correctors can either bind directly to F508del-CFTR protein (chaperones) or work by creating conditions in the cell so that higher concentrations of CFTR can be made without being degraded (proteostasis regulators). Other treatments called CFTR potentiators can then be used to improve the functioning of the CFTR protein that has been transported to the cell membrane.
Examples of CFTR correctors
The first identified CFTR correctors were Corr-4a (bisamionomethylbithiazole C4) and VRT-325 (quinazolinone C3 ). However, they are not specific for CFTR, and were found to have low efficacy and high toxicity.
This led to the development of the following next-generation correctors:
Lumacaftor (VX-809) is a CFTR corrector developed by Vertex Pharmaceuticals for the treatment of CF. Lumacaftor works by binding to the F508del-CFTR protein and preventing its degradation. While Lumacaftor showed good results in laboratory studies, it showed modest efficacy in CF patients with the F508del mutation in a Phase 2 clinical trial (NCT00865904).
Lumacaftor alone is not approved by the U.S. Food and Drug Administration (FDA) as a treatment for CF. However, a combination of lumacaftor and ivacaftor, a CFTR potentiator, is approved by the FDA and the European Commission, and marketed under the name Orkambi. The FDA’s approval of Orkambi came in 2015 following the results of three Phase 3 clinical trials, TRAFFIC (NCT01807923), TRANSPORT (NCT01807949), and PROGRESS (NCT01931839). In these trials, patients treated with Orkambi showed improvement in lung function compared with those taking a placebo.
Tezacaftor (VX-661) is a CFTR corrector similar to lumacaftor. It binds to the defective F508del-CFTR protein, then stabilizes and transports it to the cell membrane. Like lumacaftor, it is not approved on its own but is approved when used in combination with ivacaftor — a combo therapy sold under the brand name Symdeko by Vertex Pharmaceuticals.
Cavosonstat (N91115), developed by Nivalis Therapeutics, is a novel CFTR corrector that acts indirectly on the F508del-CFTR protein via proteostasis regulation. It works by inhibiting the action of an enzyme called S-nitrosogluatathione reductase (GSNOR) that regulates S-nitrosogluatathione (GSNO), a signalling molecule required for the dilation of airways. Cavosonstat boosts the low levels of GSNO seen in CF patients, which helps stabilize the CFTR protein and increase its availability in the cell.
FDL169, a CFTR corrector developed by Flatley Discovery Lab, is currently being investigated in pre-clinical studies. FDL169 works in a similar way to lumacaftor but has been found to have better drug properties and improved distribution in lungs.
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