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Research Identifies Key Hurdle in Quest for Cystic Fibrosis Treatment

Two recent studies have provided a key insight on what has been a puzzling roadblock in attempts to develop a new therapy for the majority of people with cystic fibrosis (CF). CF is an inherited disease of the glands that make mucus and sweat, with serious consequences for the lungs, pancreas, liver, intestines, sinuses, and sex organs. Thanks to the discovery of new antibiotics and improved symptom treatment, the average life expectancy for a CF patient has nearly quadrupled from about 10 years in the 1960s to about 37 years today. Indeed, some people who have CF are living into their 40s, 50s, or older. Despite these gains, life expectancy for CF patients remains much lower compared to healthy adults. CF treatment regimens can be arduous, and managing the disease can be a great challenge for patients and their families.

The development and 2012 approval of a new drug, ivacaftor, has therefore been a tremendous boon to the roughly 5 percent of people with CF who have at least 1 copy of a mutation designated G551D in CFTR, the cystic fibrosis gene. Ivacaftor was developed through a search for compounds that help stabilize the G551D version of the CFTR protein, allowing the protein to reach the cell surface and do its job. In patients with G551D, the effect of ivacaftor is to substantially alleviate many of the most serious CF symptoms. Unfortunately, researchers have not yet been successful in finding a compound that can provide a similar benefit to patients with the most common CF mutation, designated ΔF508. (Although many CFTR mutations have been identified, about 90 percent of people with CF have at least 1 copy of ΔF508.) Two recent studies identify the likely reason why an ivacaftor like approach—identification of compounds that help stabilize the ΔF508 form of the CFTR protein—has yet to benefit patients with this mutation. CFTR is a large protein with several “domains,” i.e., sections of the protein that “fold” into specific three-dimensional structures with distinct functions. The ΔF508 mutation changes a part of the CFTR protein called the first nucleotide binding domain (NBD1), eliminating a single amino acid that was previously known to be essential for proper NBD1 folding and function. The new findings show the missing amino acid also plays a key role in interaction of NBD1 with an adjacent CFTR domain, designated the 4th intracellular loop (ICL4). Using different methods, the two groups of researchers reached the same conclusion: that proper CFTR folding and function require restoration not only of proper NBD1 folding, but also stabilization of the NBD1-ICL4 interaction. Drug discovery screens to date have focused on improved NBD1 folding and function, and have not focused on improving the interaction with ICL4. Now the search is on for a drug or drug combination which corrects both of the ΔF508 structural issues. If that search is successful, the resulting treatment may one day restore significant CFTR function to people with this CF mutation, potentially reducing the burden of the disease for most people with CF, and allowing them to lead longer, healthier lives.