Dr Neil Henderson
Title: Investigation of myofibroblast αv integrins as an anti-fibrotic target in biliary atresia and fibrosis
Project Start Date: 1 October 2014
Completion Date: 30 September 2017
Biliary atresia is a devastating condition which causes inflammation and destruction of children’s bile ducts and can lead to biliary fibrosis (scarring of the liver), liver failure and death. When biliary fibrosis becomes severe, the liver begins to fail and currently our only available treatment for end-stage liver scarring is transplantation. However a shortage of donor organs means many patients die on the waiting list, and patients undergoing liver transplantation have to take immune system suppressing drugs for the rest of their life. Therefore effective new treatments for biliary atresia and fibrosis are urgently required.
Dr David Griggs, based at St. Louis University, USA, will provide all the necessary small molecule alpha v integrin antagonists as described in the proposal. This includes the synthesis of adequate amounts of the test compounds and their structural verification by mass spectrometry, verification of potency and selectivity in an in vitro panel of integrin functional assays, and pharmacokinetic analysis including quantitation of compound concentrations in plasma and tissue samples.
Myofibroblasts are specialised cells within our liver that are the major source of scar tissue during biliary fibrosis. Therefore these cells are an attractive target to study further in our search for effective new treatments for biliary atresia and fibrosis. In order to study the molecules in myofibroblasts that might be responsible for causing scar formation during biliary atresia, we will use models that allow us to remove specific molecules within myofibroblasts to see if this reduces scar formation.
Integrins are molecules which allow cells to communicate with each other and also with areas of scar within the liver. We will use models to remove a specific integrin, the alpha v integrin, from myofibroblasts to assess whether this protects from biliary fibrosis. In addition, we will use a new drug (CWHM12) that blocks alpha v integrins to assess whether this drug can protect from biliary fibrosis. We will also isolate liver myofibroblasts from patients with biliary atresia and assess whether CWHM12 can switch off scar-producing genes in these cells. This project will begin in August 2014 for 3 years, and a final report will be completed by August 2017. We will aim to disseminate our findings widely via national and international scientific meetings, high impact publications and importantly to lay audiences via multiple avenues.
Although this project is unlikely to have immediate clinical benefits, our studies will investigate whether myofibroblast alpha v integrins are key regulators of biliary fibrosis, and assess whether pharmacological targeting of alpha v integrins with a novel drug may lead to new anti-fibrotic treatments for patients with biliary atresia and also patients with other causes of biliary fibrosis (scarring). If we find that this new drug blocks fibrosis in models of biliary fibrosis, and is also able to block scar production in myofibroblasts isolated from human biliary atresia patients, then this will underpin the design of clinical trials to assess whether alpha v integrin inhibitors can block (or even
reverse) liver scarring in patients with biliary atresia, and also other causes of biliary fibrosis. If successful, this would potentially represent a major step forward in the care of these patients as it could significantly reduce the need for liver transplantation.