2006 - Optimisation of small interfering RNAs (SIRNA) targeted at the NF-kB pathway for the treatment of liver disease
Professor Derek Mann
Based: Newcastle University
Donor: GlaxoSmithKline
Amount: £114,336.00
Start date: 1st September 2006
Completed: 30th September 2009
Title of study: Optimisation of small interfering RNAs (siRNA) targeted at the NF-kB pathway for the treatment of liver disease.
Lay summary of findings
Liver fibrosis is a condition that is common to many types of chronic liver disease and involves the progressive replacement of healthy functional tissue with scar tissue. There are currently no proven effective therapies for prevention or treatment of liver fibrosis other than transplantation when the disease progresses to its end-stage of cirrhosis.
The research funded in Professor Mann’s laboratory by the British Liver Trust has made major strides towards improving our ability to develop a therapy for liver fibrosis. A specialised cell in the liver, the hepatic stellate cell, responds to injury and infection of the liver by making scar proteins. If these scar-producing cells can be encouraged to die by a process known as apoptosis, then not only are new scars prevented from being formed, but old scars appear to “melt away” to be replaced by healthy liver tissue.
The major research discovery from this grant is the existence of a series of signals that take place in the hepatic stellate cell and which combine to instruct the cell to stay alive. Most exciting is that we discovered that these signals, which include a hormone called Angiotensin II and a regulatory complex called NF-?B, can be targeted to stimulate reversion of liver fibrosis using drugs that are already proven to be safe for use in patients. One of these drugs, losartan, which is currently used for the treatment of high blood pressure, was shown to stimulate reversion of pre-existing fibrosis in 50% of patients treated for disease caused by chronic infection with hepatitis C virus.
Importantly we also discovered a chemical modification of NF-?B (Ser536 phosphorylation) that may be developed as a predictive test to determine those liver disease patients who might benefit from treatment with either losartan or similar types of medicine. There is additionally hope that Ser536 phosphorylation of NF-?B can be exploited to develop new drugs that might be even more effective than losartan. The clinical efficacy of losartan for the treatment of liver fibrosis and the potential for Ser536 phosphorylation as a new drug target in liver disease are to be determined over the next 3-5 years thanks to new funding from the MRC.
Impact of the research
The major research outcome was that describing the roles of Angiotensin II and NF-?B as stimulators of liver fibrosis. This work has already had substantial impact and is anticipated to have very strong potential for translation to the benefit of liver disease patients in the UK. The immediate impact is NIHR/MRC (EME) funding of a Newcastle-led, multi-centre, randomised clinical trial (plus associated laboratory-based science) to determine the efficacy of the angiotensin receptor blocker losartan for stimulating reversion of fibrosis in patients with fibrosis caused by non-alcoholic fatty liver disease (NAFLD). Laboratory-based work will determine if staining for the NF-?B activity marker phospho-Ser536-RelA in biopsy slides can be developed as a biomarker test for predicting patients that are likely to benefit from treatment with losartan and similar classes of drug.
The results of this trial and the biomarker research will be available around 2013 and if they show promise would lead onto larger multi-national trials aimed at establishing losartan as a treatment for reversion of liver fibrosis.
Download the full Final Report
Professor Mann's research has been published in the following scientific journals:
Gastroenterology
Angiotensin II Activates IkB Kinase Phosphorylation of RelA at Ser536 to Promote Myofibroblast Survival and Liver Fibrosis (2mb)
Editorial: Unraveling the Spider Web of Hepatic Stellate Cell Apoptosis (422kb)
Journal of Hepatology
NF-jB is a critical regulator of the survival of rodent and human hepatic myofibroblasts (1.34mb)