TMEM16A inhibitors for Cystic Fibrosis Treatment

Despite the success of CFTR modulators roughly 10% of CF patients carry rare or nonsense mutations that are not addressed by these genotype-specific drugs. Existing therapies target CFTR dysfunction but leave downstream pathology—excessive mucus secretion and chronic airway inflammation—only partially controlled. Because CF is caused by more than 2000 different mutations, a therapy from which all patients would benefit does not exist. An causal therapy would reduce these respiratory symptoms.

Both can be achieved by using compounds that inhibit the calcium-activated chloride channel TMEM16A, which plays a crucial role in both airway smooth muscle contraction and mucus formation. Among such compounds, the FDA-approved and well-tolerated antihelminthic drug niclosamide and related substances have been shown to effectively reduce mucus formation in preclinical animal studies. Its established safety profile and existing regulatory approval could significantly shorten development timelines and reduce costs compared to novel CFTR modulators.