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

New antibiotic Zavicefta approved i…

AstraZeneca today announced that the European Commission (EC) has granted marketing authorisation for Zavicefta (ceftazidime-avibactam, previously known as CAZ AVI), a ne...

Read more

Novo Nordisk and Aarhus University …

Novo Nordisk and Aarhus University's Science and Technology faculty today signed a collaboration agreement to strengthen protein technology research and development. Unde...

Read more

AstraZeneca enters licensing agreem…

AstraZeneca today announced that it has entered into agreements that support its strategic focus on three main therapy areas; Respiratory, Inflammation and Autoimmunity, ...

Read more

Novartis adds bispecific antibodies…

Today Novartis announced that it has entered into a collaboration and licensing agreement with Xencor for the development of bispecific antibodies for treating cancer. Th...

Read more

Bristol-Myers Squibb and PsiOxus Th…

Bristol-Myers Squibb Company (NYSE: BMY) and PsiOxus Therapeutics, Ltd. (PsiOxus) today announced an exclusive clinical collaboration agreement to evaluate the safety, to...

Read more

Bristol-Myers Squibb acquires Cormo…

Bristol-Myers Squibb Company (NYSE:BMY) and Cormorant Pharmaceuticals announced today that Bristol-Myers Squibb has acquired all of the outstanding capital stock of Cormo...

Read more

Sanofi Pasteur signs research agree…

Sanofi and its vaccines global business unit Sanofi Pasteur announced today a Cooperative Research and Development Agreement with the Walter Reed Army Institute of Resear...

Read more

FDA advances Precision Medicine Ini…

In support of the President’s Precision Medicine Initiative, the U.S. Food and Drug Administration has issued two draft guidances that, when finalized, will provide a fle...

Read more

Merck and Pfizer initiate Phase III…

Merck KGaA, Darmstadt, Germany, and Pfizer (NYSE: PFE) have announced the initiation of a Phase III study, JAVELIN Ovarian 100, to evaluate the efficacy and safety of ave...

Read more

Merck commits €1.5 million to the G…

Merck, a leading science and technology company, today announced it would continue to support the advancement of medical science in the field of fertility through the Gra...

Read more

Laboratory drug trials could lead t…

A new drug with the potential to reverse or slow the development of asthma is being tested by researchers at The University of Queensland. Developed by international phar...

Read more

Twisting and turning to target anti…

Researchers are getting closer to understanding how some natural antibiotics work so they can develop drugs that mimic them. A recent review commissioned by the British g...

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 ]

© World Pharma News 2006 - 2016