Affiliation:
1. Asubio Pharma Co., LTD.
Abstract
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.
Publisher
Research Square Platform LLC
Reference43 articles.
1. Cystic fibrosis genetics: from molecular understanding to clinical application;Cutting GR;HHS Public Access,2015
2. CFTR modulator therapy for cystic fibrosis;Grasemann H;N. Engl. J. Med.,2017
3. A new era in the treatment of cystic fibrosis: Correction of the underlying CFTR defect;Boyle MP;Lancet Respir. Med.,2013
4. L. CFTR genotype as a predictor of prognosis in cystic fibrosis;McKone EF;Chest,2006
5. Progress in therapies for cystic fibrosis;Boeck K;Lancet Respir. Med.,2016