Spyryx researches the roles of ENaC and SPLUNC1 in CF while seeking a cure

ENaC is the scientific notation for Epithelial Sodium Channel. The Na refers to natrium, a synonym for sodium. Sodium is the major positive ion in fluid outside of cells. The chemical notation for sodium is Na+.

ENaC is located in the apical membrane of polarized epithelial cells in particular in the kidney (primarily in the distal tubule), the lung, and the colon. In reference to Cystic Fibrosis, ENaC interaction with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is of important pathophysiological relevance.

CFTR is responsible for chloride transport and defects in this protein cause cystic fibrosis, partly through upregulation of the ENaC channel in the absence of functional CFTR.

In the airways, CFTR allows for the secretion of chloride, and sodium ions and water follow passively. However, in the absence of functional CFTR, the ENaC channel is upregulated, and further decreases salt and water secretion by reabsorbing sodium ions. As such, the respiratory complications in cystic fibrosis are not solely caused by the lack of chloride secretion but instead by the increase in sodium and water reabsorption.

This results in the deposition of thick, dehydrated mucus, which collects in the respiratory tract, interfering with gas exchange and allowing for the collection of bacteria.

Tracing timelines gives Spyryx clues to complex triggers 

1909

First mention of Na+ absorption in PubMed
(Fleisher, Hoyt & Loeb)

1951

Hans Ussing recognizes active Na+ transport
(across frog skin epithelia)

1967

First publication of the ENaC antagonist amiloride
(Eigler J, Kelter J, Renner E)

1967

John Gatzy at UNC is first person to measure ion transport in the lung
(Gatzy JT, AJP 1967)

1981

Knowles/Boucher notice increased PDs across CF nasal mucosa

1986

Boucher demonstrates increased Na+ transport in isolated CF epithelia

1990

Bernard Rossier and colleagues clone ENaC subunits

1990

Amiloride fails as a treatment for CF
(Knowles/Boucher)

1997

Ric Lifton, Rossiers and colleagues identify ENaC as cause of Liddles, PHA

1997

Bernard Rossier and colleagues clone channel activating protease 1

 1999

PLUNC 1st identified. Function unknown.
(Weston WM et al JBC 1999)

2003

Peter Di’s group identify SPURT, which turns out to be PLUNC, and find that its expression is altered in COPD patients

2004

ENaC overexpressing mouse shows spontaneous lung disease
(Mall/Boucher)

2005

PLUNC is found to be part of a larger family of related proteins and is renamed short PLUNC1 (SPLUNC1)

2009

Tarran lab find SPLUNC1 to be a regulator of ENaC
(Garcia-Cabellero et al., PNAS)

2009

SPLUNC1 protects ENaC from proteolytic cleavage.
(Cystic Fibrosis/Pulmonary Research and Treatment Center, UNC)

2011

SPLUNC1 found to be part of an even larger family of proteins and renamed BPIFA1

2011

SPLUNC1 is considered an innate material to help mucosa immunity
(Bingle L, Bingle)

2013

Tarran lab identify SPLUNC1’s ENaC inhibitory domain
(S18) (Hobbs C et al,. AJP lung 2013

2015

Spyryx LLC becomes Spyryx Biosciences C-Corp