Potential new drug target for cystic fibrosis

Potential new drug target for cystic fibrosis
Promising drug target: inhibiting DGKι reduces ENaC activity, reversing the effects of cystic fibrosis. In this assay, the green glow dims more in cells with active ENaC (bottom), so the scientists screened for cases where the cells' glow barely changed (top). Credit: EMBL/Pepperkok

Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg and Regensburg University, both in Germany, and the University of Lisboa, in Portugal, have discovered a promising potential drug target for cystic fibrosis. Their work, published online today in Cell, also uncovers a large set of genes not previously linked to the disease, demonstrating how a new screening technique can help identify new drug targets.

Cystic fibrosis is a caused by mutations in a single gene called CFTR. These mutations cause problems in various organs, most notably making the lining of the lungs secrete unusually . This leads to recurrent life-threatening , which make it increasingly hard for patients to breathe. The disease is estimated to affect 1 in every 2500-6000 in Europe.

In patients with , the mutations to CFTR render it unable to carry out its normal tasks. Among other things, this means CFTR loses the ability to control a protein called the epithelial (ENaC). Released from CFTR's control, ENaC becomes hyperactive, cells in the lungs absorb too much sodium and – as water follows the sodium – the mucus in patients' airways becomes thicker and the lining of the lungs becomes dehydrated. The only drug currently available that directly counteracts a cystic fibrosis-related mutation only works on the three percent of patients that carry one specific mutation out of the almost 2000 CFTR mutations scientists have found so far.

Thus, if you were looking for a more efficient way to fight cystic fibrosis, finding a therapy that would act upon ENaC instead of trying to correct that multitude of CFTR mutations would seem like a good option. But unfortunately, the drugs that inhibit ENaC, mostly developed to treat , don't transfer well to cystic fibrosis, where their effects don't last very long. So scientists at EMBL, Regensburg University and University of Lisboa set out to find alternatives.

"In our screen, we attempted to mimic a drug treatment," says Rainer Pepperkok, whose team at EMBL developed the technique, "we'd knock down a gene and see if ENaC became inhibited."

Starting with a list of around 7000 genes, the scientists systematically silenced each one, using a combination of genetics and automated microscopy, and analysed how this affected ENaC. They found over 700 genes which, when inhibited, brought down ENaC activity, including a number of genes no-one knew were involved in the process. Among their findings was a gene called DGKi. When they tested chemicals that inhibit DGKi in cells from cystic fibrosis patients, the scientists discovered that it appears to be a very promising drug target.

"Inhibiting DGKi seems to reverse the effects of cystic fibrosis, but not block ENaC completely," says Margarida Amaral from the University of Lisboa, "indeed, inhibiting DGKi reduces ENaC activity enough for cells to go back to normal, but not so much that they cause other problems, like pulmonary oedema."

These promising results have already raised the interest of the pharmaceutical industry and led the researchers to patent DGKi as a , as they are keen to explore the issue further, searching for molecules that strongly inhibit DGK? without causing side-effects.

"Our results are encouraging, but these are still early days," says Karl Kunzelmann from Regensburg University. "We have DGKi in our cells because it is needed, so we need to be sure that these drugs are not going to cause problems in the rest of the body."

More information: Cell, 12 September 2013. DOI: 10.1016/j.cell.2013.08.045.

Related Stories

New proteins to clear the airways in cystic fibrosis and COPD

Jul 13, 2012

University of North Carolina scientists have uncovered a new strategy that may one day help people with cystic fibrosis and chronic obstructive pulmonary disorder better clear the thick and sticky mucus that clogs their lungs ...

Unraveling a new regulator of cystic fibrosis

Sep 19, 2011

Cystic fibrosis (CF), a chronic disease that clogs the lungs and leads to life-threatening lung infections, is caused by a genetic defect in a chloride channel called cystic fibrosis transmembrane conductase regulator (CFTR). ...

Cystic fibrosis gene typo is a double whammy

Nov 12, 2010

An imbalance of salt and water in patients with cystic fibrosis makes their lungs clog up with sticky mucus that is prone to infection. The cause of the offending imbalance is a well-known genetic error, one that blocks the ...

Recommended for you

Unlocking the secrets of pulmonary hypertension

8 hours ago

A UAlberta team has discovered that a protein that plays a critical role in metabolism, the process by which the cell generates energy from foods, is important for the development of pulmonary hypertension, a deadly disease.

New molecule sneaks medicines across the blood/brain barrier

13 hours ago

Delivering life-saving drugs across the blood-brain barrier (BBB) might become a little easier thanks to a new report published in the November 2014 issue of The FASEB Journal. In the report, scientists describe an antibo ...

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.