UNMET NEED
There is understanding that mutations in the cystic fibrosis transmembrane regulator (CFTR) protein can lead to life-threatening illness. When functioning normally, CFTR is thought to be a necessary cAMP-activated chloride channel. In CF, this channel is thought to be misprocessed and retained in the endoplasmic reticulum of epithelial cells, resulting in disrupted chloride transport and the symptoms of cystic fibrosis. While ongoing clinical trials for the treatment of CF have shown promising results, further development of pharmacologic treatments for CF patients who have the ΔF508-CFTR mutation is necessary.
PROBLEM SOLVED
The most common mutation in cystic fibrosis is the deletion of phenyalanne at position 508 of the cystic fibrosis transmembrane regulator (M508-CPTR), which results in a temperature sensitive folding defect and premature degradation by the ubiquitin proteasome system. JHU researchers have demonstrated that inhibition of the proteasome with Bortezomib (PS-341/Velcade) promoted accumulation of immature CPTR in the ER and partial rescue of functional chloride channels to the cell surface. In addition, proteasome inhibition suppressed levels of (IL)-8, the major inflammatory cytokine in cystic fibrosis.
STAGE OF DEVELOPMENT
The inventors have identified compounds and methods for treatment of CF via modulation of the endoplasmic reticulum associated degradation pathway.
The inventors have demonstrated that CFTR chloride transport can be rescued by administration of PS-341, resulting in enhancement of CFTR trafficking to the cell surface.
Additionally, the inventors have demonstrated that PS-341 suppresses expression of IL-8, the major inflammatory cytokine in CF.
PUBLICATIONS & PATENTS
Vij, Neeraj, Shengyun Fang, and Pamela L. Zeitlin. "Selective Inhibition of Endoplasmic Reticulum-associated Degradation Rescues ΔF508-Cystic Fibrosis Transmembrane Regulator and Suppresses Interleukin-8 Levels THERAPEUTIC IMPLICATIONS." Journal of Biological Chemistry 281.25 (2006): 17369-17378.
US Issued Patent 8,273,700
