Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common of the nearly 1,200 known CFTR mutations causes the deletion of a single amino acid at position 508 (ΔF508) in the protein sequence; this is found in nearly 70 percent of CF patients.
CFTR is an ion channel protein on the cell surface that regulates the flow of chloride ions and water in and out of the cells. The most characteristic feature of CF is thick and sticky mucus secretions in the lungs, pancreas, and other organs. CF patients experience persistent lung infections and inflammation because of clogged airways that trap bacteria and other pathogens. This eventually leads to respiratory failure and can be life-threatening.
There are several therapeutic avenues available to treat and manage CF symptoms. CFTR amplifiers are a new class of medications that increase CFTR protein levels in cells and tissues. They are being tested for clinical use in combination with other CFTR modulators such as potentiators (ivacaftor and PTI-808), and correctors (lumacaftor, tezacaftor, and PTI-801) to alleviate symptoms of CF.
How CFTR amplifiers work
In CF patients with the ΔF508 mutation, very little CFTR protein is found on the cell surface because most of it is degraded. This reduces the efficacy of treatments that improve the function of the mutant CFTR protein such as CFTR correctors and potentiators. Amplifiers increase the amount of mutant CFTR messenger RNA, and consequently the amount of CFTR protein, thereby increasing the substrates for other CFTR modulators. Messenger RNA is an intermediate molecule containing a copy of the genetic code specifying the amino acid sequence of a protein.
CFTR amplifiers in clinical trials
A Phase 2 clinical trial (NCT02718495) showed that PTI-428 can improve lung function in CF patients receiving Orkambi (a combination treatment consisting of lumacaftor and ivacaftor) with no significant adverse effects.
A Phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT03591094) is under way to assess the therapeutic effects of PTI-428 in CF patients who have two copies of the ΔF508 mutation and are currently being treated with tezacaftor/ivacaftor (Symdeko, known as Symkevi in the European Union).
A Phase 1/2, randomized, double-blind, placebo-controlled study (NCT03500263) is recruiting patients in the U.K. to evaluate the safety, tolerability, and pharmacokinetics (movement in the body) of a combination therapy with PTI-808, PTI-801, and PTI-428 in CF patients with either two copies of the ΔF508 mutation or two different mutations in the CFTR gene, one of them being the ΔF508 mutation.
Researchers at Proteostasis Therapeutics conducted a high-throughput screen (HTS) to identify novel small molecule modulators that act on the CFTR protein. They identified a novel small molecule amplifier, PTI-CH, which improves the efficacy of treatment with ivacaftor and lumacaftor (Orkambi) two-fold.
PTI-CH showed amplifier activity in primary cells derived from both lung and non-lung tissues and when given to animals orally. The precise mechanism by which PTI-CH selectively increases CFTR mRNA levels and protein levels is being still investigated.
Researchers have also shown that PTI-CH enhances the therapeutic effects of Orkambi in bronchial cell lines and nasal cultures obtained from patients who have a rare CFTR mutation, which produces dysfunctional CFTR protein with altered channel function in a manner similar to the common ΔF508-CFTR mutation.
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