Data from Alex Keen - Curated by EPG Health - Last updated 11 April 2018
This year’s ILC is being held from 11‒15 April 2018 in Paris, hosting a number of educational, abstract and industry sessions involving various aspects of liver disease. The Basic Science Seminar for 2018 is focused on targetable pathways in liver disease, covering pathway identification, potential drug targets and their clinical application. Studies authored by a number of experts speaking at this year’s session are discussed below, telling the story from drug target identification to the clinical application of novel therapies and techniques.
The identification of targetable pathways in liver disease is imperative for the development of new therapies able to influence disease in a novel way. There are several methods to identify targetable pathways, from big data analysis, through organ and tissue investigation, down to the cellular and molecular levels.
Big data is a relatively new and rapidly expanding approach to drug discovery. Extensive data are collected in an unbiased manner and subsequently analysed to reveal trends and patterns. These databases can contain information on chemical substances, disease targets and clinical information which can be used to mitigate the time and resource heavy nature of target identification and drug discovery. An example that highlights the benefits of big data analysis in medicine was the identification of a sub-population of NSCLC patients, where 5% had a specific mutation in the ALK gene. This led to the rapid development, testing and approval of crizotinib, an ALK inhibitor, for use in NSCLC only a few years after the initial discovery of the mutation, dramatically cutting development costs, reducing time to market and improving prognosis.
Once these potential targets have been identified, research must be undertaken to ascertain which, if any, agents can act on them producing a superior therapeutic effect. Bile acids are an essential component of bile, a liquid produced by the liver to breakdown lipids, but also play an important role as signalling molecules and metabolic regulators. Antonio Moschetta has authored several studies into the suitability of bile acid receptors as drug targets. One such study investigated FXR, a nuclear receptor that is activated by bile acids and controls their production. In cholestasis, a disorder characterised by an excess of bile acids in the liver and a deficit in the intestine, the researchers found that FXR activation in the intestine reduced bile acid production in the liver, helping to mitigate toxic effects of excess bile. This interesting result suggests that the intestine could be treated in order to protect the liver, opening up a large number of new treatment targets and pathways to be exploited.
Next, these newly discovered pathways need to be applied to clinical practice, whether this be in a therapeutic or diagnostic setting. ‘Liquid biopsies’ are a novel diagnostic technique that offer a simple blood test to diagnose a whole range of conditions, especially cancers and diseases like liver fibrosis. Currently the most accurate method to assess the condition of the liver is with a biopsy, an invasive procedure associated with relatively high risk and discomfort for the patient. A team led by Jelena Mann investigated new methods of assessing disease progression in patients with liver fibrosis in NAFLD. Currently, liver biopsy is used to assess fibrosis, where a tissue sample is taken and certain biomarkers are analysed. This new research has explored the possibility that these biomarkers could also be detected as they circulate in the blood, providing a credible, non-invasive alternative for fibrosis stratification. Their results suggest that these biomarkers can be detected and that they correlate with the stage of liver fibrosis. With validation, this ‘liquid biopsy’ technique could become a very useful clinical tool, improving diagnostic accuracy and reducing the need for invasive procedures.
Once an accurate diagnosis has been made, the correct treatment needs to be selected and administered. Nanomedicine is an exciting field that combines the latest in nanotechnology with medical practice, offering targeted drug delivery methods that are able to deposit the treatment precisely in the diseased region of the body, greatly reducing side effects and off-target toxicity. A recent study from Leonard Kaps and colleagues has suggested that nanohydrogel particles can be used to administer agents that modify gene expression to diseased areas of the liver. The enhanced particles that Kaps’ team created are better able to remain stable, show good specificity to the liver, and are able to successfully target a gene that produces collagen, reducing its expression and generating an antifibrotic effect in the mouse models. This is an exciting method of specific and sustained drug delivery within the rapidly growing field of nanomedicines, opening the door to therapies that would otherwise be too fragile, small or toxic to use.
The hope is that the use of new technologies and techniques will expedite drug discovery and development, creating more effective and personalised medicines that are able to act with greater efficacy and in a more specific manner. The sessions at ILC 2018 will cover the topics discussed here, plus many more, highlighting current and future advances to rapidly translate pathogenic mechanisms into novel clinical applications.
Resources & further reading
Horizons article on epgonline.org: Improving non-alcoholic steatohepatitis care – is the finishing line in sight?
Gerber D, Minna J. ALK Inhibition for Non-Small Cell Lung Cancer: From Discovery to Therapy in Record Time. Cancer Cell. 2010; 18(6):548–551.
Hardy T, Zeybel M, Day CP, et al. Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut. 2017; 66(7):1321–1328.
Kim R, Goossens N, Hoshida Y. Use of big data in drug development for precision medicine. Expert Rev Precis Med Drug Dev. 2016; 1(3):245–253.
Lambrecht J, et al. Prospects in non-invasive assessment of liver fibrosis: Liquid biopsy as the future gold standard? Biochim Biophys Acta. 2018; 1864(4 Pt A):1024–1036.
Pavlovic N, Stanimirov B, Mikov M. Bile Acids as Novel Pharmacological Agents: The Interplay Between Gene Polymorphisms, Epigenetic Factors and Drug Response. Curr Pharm Des. 2017; 23(1):187–215.