SPX-101 is a Novel ENaC-targeted Therapeutic for Cystic Fibrosis that Restores Mucus Transp

SCOTT, DAVID; WALKER, MATHEW; JULIANA SESMA; WU, BRYANT; STUHLMILLER, TIMOTHY; CROWDER, TIMOTHY; TARRANT, ROBERT

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

AMER THORACIC SOC

Año: 2017

1073-449X

AbstractRATIONALE:Cystic Fibrosis lung disease (CF) is caused by the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) combined with hyperactivation of the epithelial sodium channel (ENaC). In the lung, ENaC is responsible for movement of sodium which creates an osmotic gradient that pulls fluid out of the airway. Hyperactivation of ENaC contributes to reduced airway hydration causing mucus dehydration, decreased mucociliary clearance, and chronic bacterial infections. ENaC represents a therapeutic target to treat all CF patients independent of their underlying CFTR mutation.OBJECTIVE:To investigate the in vitro and in vivo efficacy of SPX-101, a peptide mimetic of SPLUNC1´s natural regulatory function that controls ENaC activity.METHODS:ENaC internalization by SPX-101 in primary human bronchial epithelial cells from healthy and CF donors was assessed by surface biotinylation and subsequent western blot analysis. SPX-101´s in vivo therapeutic effect was assessed on survival of βENaC transgenic mice, mucus transport in these mice, and mucus transport in a sheep model of CF.MEASUREMENTS AND MAIN RESULTS:SPX-101 binds selectively to ENaC and promotes internalization of the α, β, and γ subunits. Removing ENaC from the membrane with SPX-101 causes a significant decrease in amiloride-sensitive current. The peptide increases survival of βENaC transgenic mice to >90% with once-daily dosing. SPX-101 increased mucus transport in the βENaC mouse model as well as the sheep model of CF.CONCLUSIONS:These data demonstrate that SPX-101 promotes durable reduction of ENaC membrane concentration leading to significant improvements in mucus transport.