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Nov 29, 2012
 |  BC Innovations  |  Targets & Mechanisms

Sponging out cystic fibrosis

A Canadian team has found that compounds from sea sponges could be useful for treating cystic fibrosis. The compounds work in part by inhibiting a new family of targets for the disease: poly(ADP-ribose) polymerases.1 The researchers now plan to work backward to uncover why blocking these polymerases improves the function of cystic fibrosis transmembrane conductance regulator, the mutated protein that causes cystic fibrosis.

CF results from loss-of-function mutations in cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel that helps lubricate the epithelial lining of lungs, pancreas and intestine. Patients who inherit two mutated copies of CFTR develop thick mucus and are prone to severe respiratory infections and digestive problems.

The most common CF-associated CFTR mutation, DF508, is a genetic deletion of a single amino acid within the protein. Whereas wild-type CFTR functions on the cell surface, the DF508 protein is flagged as defective by cellular quality control mechanisms and becomes trapped in the endoplasmic reticulum (ER).

Notably, the DF508 version of CFTR can still function as an ion channel if it can make it to the cell surface. Thus, one therapeutic strategy has been to find compounds that change the ER's metabolism to allow the mutant CFTR to proceed to the cell surface.

An alternative strategy, pursued by Vertex Pharmaceuticals Inc., is to hit mutant CFTR directly with molecules that fix its structure, allowing the defective protein to pass muster with the ER quality control system.

Since 2001, a team led by David Thomas, chair of the Department of Biochemistry at McGill University, also has run screens in collaboration with GlaxoSmithKline plc to find small molecules that improve cell surface expression of CFTR.

Now, the McGill team has...

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