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 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 new-borns 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.’ EMBL

Genes have an influence on whether we are left handed or right handed.

A genetic study has identified a biological process that influences whether we are right handed or left handed.
Scientists at the Universities of Oxford, St Andrews, Bristol and the Max Plank Institute in Nijmegen, the Netherlands, found correlations between handedness and a network of genes involved in establishing left-right asymmetry in developing embryos.
‘The genes are involved in the biological process through which an early embryo moves on from being a round ball of cells and becomes a growing organism with an established left and right side,’ explained first author William Brandler, a PhD student in the MRC Functional Genomics Unit at Oxford University.
The researchers suggest that the genes may also help establish left-right differences in the brain, which in turn influences handedness.
Humans are the only species to show such a strong bias in handedness, with around 90% of people being right-handed. The cause of this bias remains largely a mystery.
The researchers, led by Dr Silvia Paracchini at the University of St Andrews, were interested in understanding which genes might have an influence on handedness, in order to gain an insight into the causes and evolution of handedness.
The team carried out a genome-wide association study to identify any common gene variants that might correlate with which hand people prefer using.
The most strongly associated, statistically significant variant with handedness is located in the gene PCSK6, which is involved in the early establishment of left and right in the growing embryo.
The researchers then made full use of knowledge from previous studies of what PCSK6 and similar genes do in mice to reveal more about the biological processes involved.
Disrupting PCSK6 in mice causes ‘left-right asymmetry’ defects, such as abnormal positioning of organs in the body. They might have a heart and stomach on the right and their liver on the left, for example.
The researchers found that variants in other genes known to cause left-right defects when disrupted in mice were more likely to be associated with relative hand skill than you would expect by chance.
While the team has identified a role for genes involved in establishing left from right in embryo development, William Brandler cautioned that these results do not completely explain the variation in handedness seen among humans. He said: ‘As with all aspects of human behaviour, nature and nurture go hand-in-hand. The development of handedness derives from a mixture of genes, environment, and cultural pressure to conform to right-handedness.’
This work was supported by the University of St Andrews, the UK Medical Research Council, the Wellcome Trust, the Max Plank Society, and the EU 6th Framework Programme. University of Oxford

Autism spectrum disorders (ASD) are an increasingly diagnosed group of neurodevelopmental disorders. Although heritability suggests a strong genetic component, efforts to identify genes involved have had disappointing results, and the difference in disease state between identical (monozygotic) twins points to a potential role for epigenetic factors. Two new studies have found a significant correlation between DNA methylation (DNAm) patterns and ASD traits. Wong et al. performed a genome-wide analysis of DNAm in a sample of 50 monozygotic twin pairs sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype [1]. Numerous differentially methylated regions associated with ASD were identified and significant correlations between DNAm and quantitatively measured autistic trait scores were reported. Ladd-Acosta et al. examined DNAm in post-mortem brain tissue from 19 autism cases and 21 unrelated controls. Over 485 000 CpG loci were measured across a diverse set of functionally relevant genomic regions and four genome-wide significant differentially methylated regions were identified [2].

<sub>1. Wong et al. Mol Psychiatry 2013; doi: 10.1038/mp.2013.114 (www.nature.com/mp/journal/vaop/ncurrent/full/mp201341a.html).
2. Ladd-Acosta et al. Mol Psychiatry 2013; doi: 10.1038/mp.2013.114 (www.nature.com/mp/journal/vaop/ncurrent/full/mp2013114a.htm).</sub>

BD Diagnostics and the College of American Pathologists (CAP) have announced the launch of a new strategic alliance that will provide solutions to advance laboratory quality for improved patient outcomes in China and India. BD and CAP announced the collaboration during the American Association for Clinical Chemistry (AACC) Annual Meeting in Houston, Texas.

Laboratories play a critical role in the diagnosis and treatment of disease for the more than 2.5 billion people who live in China and India. The BD/CAP Strategic Alliance will improve access to external quality assurance/proficiency testing (PT) that can have a direct and positive impact on laboratory quality, and therefore, patient outcomes. Together BD and CAP will provide education to improve awareness of global practice standards and training that will help laboratories achieve their quality improvement goals. Additionally, BD will manage PT distribution, including sales, shipping, and first-line client service.

“The clinical laboratory and pathology contribute more than 70 percent of the information used to determine diagnoses and drive treatment decisions,” said CAP President Stanley J. Robboy, MD, FCAP. “CAP has all of the tools necessary to help laboratories improve and monitor efforts that drive quality performance. This strategic alliance with BD will increase access to these essential resources, helping laboratories accelerate their quality improvement journey so that they can contribute to better quality care, differentiate themselves and their institutions, and be recognized globally among the best providers of laboratory and pathology services.”

CAP’s Laboratory Accreditation, Surveys, PT programmes, and other quality management resources combined with BD’s in-depth clinical knowledge of preanalytical systems provide a comprehensive, expert-based toolkit to help laboratories in China and India continuously improve the quality of the testing services they provide to patients. Through participation in CAP accreditation, laboratories in China and India can demonstrate their compliance to the most robust and comprehensive clinical laboratory testing standards in the world.
Having operated in China since 1994 and in India since 1996 supporting public and private sector partners in enhancing laboratory standards, BD has extensive experience in deploying clinical expertise and educational resources in these regions, as well as a deep understanding of the unique needs of laboratories throughout these countries. Today in China, there are 18 CAP-accredited laboratories and nearly 100 laboratories participating in PT. In India, of the 71 laboratories participating in CAP PT, 42 have achieved CAP accreditation. BD’s access and logistics experience will support CAP PT importation and ensure more timely delivery and quality, reduce participants’ administrative work, and allow billing in local currency. Market launch of this initiative will begin in China and India in August 2013 with PT distribution initiated in January 2014.

Diagnostica Stago S.A.S, a privately held company that provides reference tests and instrumentation in hemostasis, announced that the company has entered a joint research agreement with Bristol-Myers Squibb Company (BMY) to develop an assay for measuring the circulating blood concentration of the oral Factor Xa inhibitor ELIQUIS (apixaban). No commercial assay is presently available to specifically measure apixaban plasma concentration. Terms of the agreement were not disclosed.

“Stago is pleased to have the opportunity to develop this test”, said Tristan Herve, Director of Pharmaceutical Development, “These oral Factor Xa inhibitors address an important unmet need for patients requiring anticoagulant therapy”.

Stago has already completed prototype development and will be applying for health authority approvals of the assay worldwide. Diagnostica Stago retains 100 percent global development and commercialization rights for the assay.