(provided by the applicant): Cystic fibrosis (CF) is the most common, life limiting autosomal recessive genetic disease in the US. CF airways contain abundant IL-8, the most active known pro-inflammatory cytokine. The IL-8 in the CF airway is derived from epithelial cells, and the resulting high levels of IL-8 attract neutrophils and other inflammatory cells. IL-8 hypersecretion in the CF lung results from a dysfunctional tumor necrosis factor alpha/nuclear factor-kappa B (TNFa/NF?B) signaling pathway. For that reason an attractive pharmaceutical strategy has been to find a drug that would suppress that part of the pathway involved in IL-8 expression, but not other parts required for physiological responses to infection. Recently, low concentrations of the drug digitoxin have been discovered to suppress IL-8 hypersecretion by CF lung epithelial cells (Srivastava et al PNAS, 2004). The mechanism of digitoxin action is to suppress the TNFa/NF?B signaling pathway. Digitoxin specifically blocks the interaction between the TNF receptor and the adaptor protein (Yang et al, PNAS 2005). This site of interaction is known as the initiator for assembly of a set of three other adaptor proteins, the "inflammasome" which leads downstream to IL-8 expression. The oral bioavailability of digitoxin is approximately 100%, and therefore the applicants have hypothesized that digitoxin will safely suppress IL-8 dependent lung inflammation when administered orally to cystic fibrosis patients. The purpose of this proposal is to test this hypothesis and find a safe and tolerable dose.

Public Health Relevance

Cystic Fibrosis (CF) is the most common, life limiting autosomal recessive genetic disease in the U.S., with a prevalence of ca. 30.000 total patients. The CF airway constitutively secretes Il-8 which attracts neutrophils and sustains a high level of inflammation. We will test the safety and efficacy of low doses of the cardiac glycoside digitoxin to suppress CF airways inflammation.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project (R01)
Project #
5R01FD003456-03
Application #
8238123
Study Section
Special Emphasis Panel (ZFD1-OPD-N (S1))
Project Start
2008-09-20
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2012
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218