Bypassing CFTR dysfunction in cystic fibrosis with alternative pathways for anion transport

Abstract

One therapeutic strategy for cystic fibrosis (CF) seeks to restore anion transport to affected epithelia by targeting other apical membrane Cl^- channels to bypass dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl^- channel. The properties and regulation of the Ca²⁺-activated Cl^- channel TMEM16A argue that long-acting small molecules which target directly TMEM16A are required to overcome CFTR loss. Through genetic studies of lung diseases, SLC26A9, a member of the solute carrier 26 family of anion transporters, has emerged as a promising target to bypass CFTR dysfunction. An alternative strategy to circumvent CFTR dysfunction is to deliver to CF epithelia artificial anion transporters that shuttle Cl^- across the apical membrane. Recently, powerful, non-toxic, biologically-active artificial anion transporters have emerged.