Science and Technology Production
Congress
Authorship
Date
2017
Publishing House and Editing Place
A
Summary
Information provided by the agent in
SIGEVA
Background: Airway epithelial cells secrete Short Palate, Lung, and Nasal Clone 1 (SPLUNC1), which regulates epithelial sodium channel (ENaC) activity by lowering the number of channels on the cell surface. However, SPLUNC1 loses this regulatory function at the acidic pH of the cystic fibrosis (CF) airway leading to hyperactivation of ENaC. When ENaC becomes hyperactivated, the increased sodium transport creates an osmotic gradient that pulls fluid out of the airway. Loss of airway fluid causes...
Background: Airway epithelial cells secrete Short Palate, Lung, and Nasal Clone 1 (SPLUNC1), which regulates epithelial sodium channel (ENaC) activity by lowering the number of channels on the cell surface. However, SPLUNC1 loses this regulatory function at the acidic pH of the cystic fibrosis (CF) airway leading to hyperactivation of ENaC. When ENaC becomes hyperactivated, the increased sodium transport creates an osmotic gradient that pulls fluid out of the airway. Loss of airway fluid causes mucus dehydration, decreased mucociliary clearance, and chronic bacterial infections which account for the majority of morbidity and mortality associated with CF. ENaC represents a promising therapeutic target that could treat all CF patients independent of their underlying CFTR mutation. We have developed a peptide mimetic of SPLUNC1, SPX-101, that retains ENaC regulatory function even at acidic pH.Objectives: To determine in vitro and in vivo effectiveness of SPX-101 in CF-like lung disease and assess the safety of the peptide when delivered by nebulization.Results: SPX-101 induced ENaC internalization in primary human bronchial epithelial cells (HBEC) derived from both healthy and CF donors as assessed by surface biotinylation experiments. This novel internalization mechanism reduced channel density and caused a loss in amiloride sensitive current in HBECs. In-vivo, SPX-101 increased mouse survival, corrected leukocyte distribution in broncho-aveolar lavage fluids, and increased mucus movement in the βENaC transgenic mouse model of CF. Using a sheep model where CFTR inhibitor is delivered to the upper airway via nebulization, thereby decreasing mucus movement by ~50%, SPX-101, but not small molecule inhibitors of ENaC such as amiloride, fully restored mucus transport. Lastly, a 28-day GLP toxicology assessment of nebulized SPX-101 showed no adverse effects. Importantly, there were no observed diuretic or electrolyte altering effects of SPX-101 up to the maximum deliverable dose.Conclusion: SPX-101 increases mucus transport in multiple models of CF-like lung disease. The peptide has low systemic availability and no observed adverse effects. Taken together, SPX-101 represents a novel peptide-based therapy to treat all patients with CF regardless ofCFTR mutation.Funding: Research was funded in part by a grant from the Cystic Fibrosis Foundation.
Show more
Show less
Key Words
CYSTIC FIBROSIS