Targeted therapy in portal hypertension

• 
  Doctor
  Chandana Herath

  cherath@unimelb.edu.au

  +61 3 9496 2403

Project Details

Cirrhosis is a major cause of death in Australia and affects over 300 million people worldwide. Approximately 90% of cirrhotic patients eventually develop portal hypertension (PHT). A major complication of PHT is the formation of gastrointestinal varices (swollen veins); bleeding from which accounts for much of the mortality and morbidity in cirrhotic patients. Current ‘gold standard’ therapy to prevent variceal bleeding is treatment with non-selective beta-blockers (NSBBs) which act by reducing cardiac output. However, approximately 15% of cirrhotic patients are intolerant to treatment with NSBBs, and up to 60% fail to achieve the treatment response required to prevent variceal bleeding defined as a fall in estimated portal pressure of greater than 20% or a fall in the hepatic venous pressure gradient to <12 mmHg. Therefore, it is imperative that more effective and specific therapies with fewer systemic side effects are developed for the prevention and treatment of PHT.
We have made a pioneering contribution showing that the renin angiotensin system (RAS) plays a central role in the pathogenesis of PHT. In subsequent studies, we have shown that angiotensin-(1-7) peptide levels are elevated in the liver and circulation of cirrhotic animals and cirrhotic patients, and that angiotensin-(1-7) contributes to PHT by acting via the MasR to increase mesenteric vasodilatation and mesenteric blood flow in cirrhosis.

Our recent discovery of the existence of a new vasodilatory renin angiotensin system (RAS) receptor, the Mas-related G protein-coupled receptor-type D (MrgD), in the cirrhotic mesenteric vasculature is of major potential importance because MrgD blockade produced a massive 33% reduction in portal pressure in cirrhotic rats compared to a 21% reduction with previously known MasR blockade or the 20% reduction with NSBBs in patients. Importantly, we have shown that this effect was specific to the mesenteric vasculature.

We have therefore initiated a program of research to develop novel therapeutics for the prevention and treatment of PHT as there have been no new drug classes introduced for the long-term management of PHT for more than 30 years. To enable this work, in collaboration with ORACLE Australia, we have developed the fastest drug screening pipeline in Australia to screen small molecules for drug development (https://blogs.oracle.com/research/post/drug-discovery-at-warp-speed-oracle-cloud-makes-it-so). Our drug screening pipeline is currently being utilised to screen over 750 million small molecules from the ZINC database using the MrgD homology model we developed. Whilst in silico drug screening is ongoing, we have identified a few molecules which are currently undergoing robust in vitro testing including on-rate and off-rate binding affinity studies followed by in vivo preclinical studies to determine oral bioavailability, in vivo metabolism, excretory profiles/pathways and animal toxicity studies.

Researchers

• Dr Chandana Herath – Senior Research Fellow
• Prof Peter Angus

Collaborators

• A/Prof Anthony Zulli, School of Biomedical Sciences, Victoria University, Australia
• Dr Harinda Rajapaksha, Oracle Australia
• Prof Jonel Trebicka, University Clinic Frankfurt, Germany
• Dr John Bruning, University of Adelaide, Australia
• Prof Raymond Norton, Monash University, Australia
• Prof Arthur Christopoulos, Monash University, Australia

Funding

• National Health and Medical Research Council (NHMRC) of Australia
• Austin Medical Research Foundation (AMRF)

Research Opportunities

This research project is available to PhD students, Masters by Research, Honours students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.

Research Outcomes

Our studies will establish a fundamental role of MrgD in PHT and will lead to the development of more effective targeted treatments to markedly reduce portal pressure in cirrhotic patients with PHT with minimal unwanted systemic side-effects.

Research Publications

• Gunarathne LS, Rajapaksha IG, Casey S, Qaradakhi T, Zulli A, Rajapaksha H, Trebicka J, Angus PW, Herath CB. (2022). Mas-related G protein-coupled receptor type-D (MrgD) antagonism improves portal hypertension in cirrhotic rats. Hepatology Communications Sep;6(9):2523-2537.
• Herath CB, Angus PW, Trebicka J. (2022). Portal Hypertension in Cirrhosis: From Pathogenesis to Novel Treatments. EDITORIAL. Frontiers in Physiology 2022 Mar 21;13:864083.
• Rajapaksha IG, Gunarathne LS, Angus PW, Herath CB. Update on new aspects of the renin-angiotensin system in hepatic fibrosis and portal hypertension: Implications for novel therapeutic options. (2021) REVIEW. Journal of Clinical Medicine 2021 Feb 6, 10(4), 702.
• Warner FJ, Rajapaksha H, Shackel N, Herath CB. ACE2: from protection of liver disease to propagation of COVID-19. (2020) REVIEW. Clinical Science (London) Dec 11;134(23):3137-3158.
• Gunarathne LS, Angus PW, Herath CB. (2019). Blockade of Mas Receptor or Mas-Related G-Protein Coupled Receptor Type D Reduces Portal Pressure in Cirrhotic but Not in Non-cirrhotic Portal Hypertensive Rats. Frontiers in Physiology Sep 20;10:1169.
• Mak KY, Chin R, Cunningham S, Habib MR, Toressi J, Sharland AF, Alexander IE, Angus PW, 4. Herath CB. (2015). ACE2 gene therapy using adeno-associated viral vector inhibits liver fibrosis in mice. Molecular Therapy 23(9): 1434-1443.
• Grace JA, Klein S, Herath CB, Granzow M, Schierwagen R, Masing N, Walther T, Sauerbruch T, Burrell LM, Angus PW, Trebicka J. (2013). Activation of the Mas receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis. Gastroenterology 145(4):874-884.