Mutation-independent cystic fibrosis treatment by opening calcium-activated chloride channel with a novel GPR39 agonist, DS-1039

Abstract Cystic fibrosis (CF) is a life-limiting genetic disease characterized by decreased chloride and water secretion and caused by loss-of-function mutations in CF transmembrane conductance regulator (CFTR), an epithelial chloride channel. Here, we report DS-1039, an orally active GPR39 agonist, as a novel pharmacological agent to rescue CFTR dysfunction by activating calcium-activated chloride channel (CaCC). DS-1039 induced sustained chloride secretion and fluid transfer in primary bronchial epithelial cells from CF patients. DS-1039 activity was comparable to that of ivacaftor and lumacaftor in mutations with indications for these CFTR modulators, and even observed in class I mutations without approved CFTR modulators. DS-1039 oral administration to mice induced significant tear secretion. Combined with human pharmacokinetics (PK) projection and PK/pharmacodynamics relationship analysis, it was suggested that GPR39 agonists could induce fluid transfer in humans at practical doses. These findings highlight DS-1039 as a promising novel oral agent for CF treatment independent of CFTR mutation.