Research

Potential new drug target for cystic fibrosis

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 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 hereditary disease 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 thick mucus. This leads to recurrent life-threatening lung infections, which make it increasingly hard for patients to breathe. The disease is estimated to affect 1 in every 2500-6000 newborns in Europe.

In patients with cystic fibrosis, 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 sodium channel (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 hypertension, 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 lung 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 drug target, as they are keen to explore the issue further, searching for molecules that strongly inhibit DGKi 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."

The search for genes that regulate ENaC was undertaken as part of the EU-funded TargetScreen2 project.

Joana Almaça et al. High-Content siRNA Screen Reveals Global ENaC Regulators and Potential Cystic Fibrosis Therapy Targets. Published online in Cell on 12 September 2013. DOI: 10.1016/j.cell.2013.08.045.

Most Popular Now

Boehringer Ingelheim increases acce…

Boehringer Ingelheim is announcing an expansion of its Intellectual Property (IP) enforcement policy. The IP enforcement policy had already been amended in 2007 by an eas...

Read more

AstraZeneca licenses Zurampic to Gr…

AstraZeneca today announced that it has entered into a licensing agreement with Grünenthal GmbH for the exclusive rights to Zurampic (lesinurad) in Europe and Latin Ameri...

Read more

Pfizer presents promising data from…

Pfizer Inc. (NYSE:PFE) today announced encouraging new data from a Phase 1/2 study of lorlatinib, the proposed generic name for PF-06463922, Pfizer's investigational, nex...

Read more

Bayer Science & Education Found…

Applications for the Bayer Science & Education Foundation's international scholarship programs are now being accepted for this year's round. In the academic sector, ambit...

Read more

Merck announces survey results expl…

Merck, a leading science and technology company, today announced survey results of 250 global biopharmaceutical executives on how their companies will manage new risks as...

Read more

Merck Accelerator expands its reach…

Merck, a leading science and technology company, has started this week the application period for the next round of its Accelerator programs in Darmstadt, Germany, and Na...

Read more

AstraZeneca enters commercialisatio…

AstraZeneca today announced it has entered into a commercialisation agreement with Aspen Global Incorporated (AGI), part of the Aspen Group, for rights to its global anae...

Read more

Promising treatment prospects for i…

In Switzerland alone, more than 5,700 women are diagnosed with breast cancer each year, and almost 1,400 of those affected die of the disease. In many very invasive forms...

Read more

Call for Abstracts: DIA EuroMeeting…

29 - 31 March 2017, Glasgow, UK. The DIA EuroMeeting 2017 provides a platform for experts from all relevant disciplines within the entire healthcare development and acce...

Read more

Boehringer Ingelheim and Harvard sc…

Boehringer Ingelheim today announced it has established a research collaboration with the Harvard Stem Cell Institute's - Harvard Fibrosis Network to discover new ways of...

Read more

FDA targets unlawful internet sales…

The U.S. Food and Drug Administration, in partnership with international regulatory and law enforcement agencies, announced that it took action this week against 4,402 we...

Read more

New class of protein could treat ca…

A protein designed by researchers at Georgia State University can effectively target a cell surface receptor linked to a number of diseases, showing potential as a therap...

Read more

Digest World Pharma Newsletter

Subscribe to our weekly Digest World Pharma Newsletter and stay updated on the latest World Pharma News. Subscribe now, it's free!

Pharmaceutical Companies

[ A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Z ]