SPX-101 Is a Novel Epithelial Sodium Channel-targeted Therapeutic for Cystic Fibrosis That Restores Mucus Transport.

Abstract:

RATIONALE:Cystic fibrosis (CF) lung disease 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. Hyperactivation of ENaC, which creates an osmotic gradient that pulls fluid out of the airway, contributes to reduced airway hydration, causing mucus dehydration, decreased mucociliary clearance, and recurrent acute bacterial infections. ENaC represents a therapeutic target to treat all patients with CF independent of their underlying CFTR mutation. OBJECTIVES:To investigate the in vitro and in vivo efficacy of SPX-101, a peptide mimetic of the natural regulation of ENaC activity by short palate, lung, and nasal epithelial clone 1, known as SPLUNC1. 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 by survival of β-ENaC-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 β-ENaC-transgenic mice to greater than 90% with once-daily dosing by inhalation. SPX-101 increased mucus transport in the β-ENaC 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.

authors

Scott DW,Walker MP,Sesma J,Wu B,Stuhlmiller TJ,Sabater JR,Abraham WM,Crowder TM,Christensen DJ,Tarran R

doi

10.1164/rccm.201612-2445OC

subject

Has Abstract

pub_date

2017-09-15 00:00:00

pages

734-744

issue

6

eissn

1073-449X

issn

1535-4970

journal_volume

196

pub_type

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