Hepatology and Gastroenterology Research Group

Research Overview

Targeted ACE2 gene therapy in liver fibrosis

Cirrhosis (severe liver scaring) of the liver is a leading cause of morbidity and mortality in our community and its prevalence is rising. While remedies targeting liver scaring will have some beneficial effects in reducing this disease burden, there remains a major need to develop drugs that can be used to prevent the progression of liver scarring and cirrhosis.

Our NHMRC-funded studies provided the first empirical evidence that in liver disease there is an activation of the ‘alternate RAS’ in which angiotensin converting enzyme 2 (ACE2) degrades potent hypertensive and pro-fibrotic peptide angiotensin II and generates anti-fibrotic peptide angiotensin-(1-7). In contrast to angiotensin II, angiotensin-(1-7) has potent vasodilatory properties mediated by its putative receptor, MasR. These pioneering discoveries formed the basis of our ongoing translational research which encompasses basic science discoveries in animal models of liver disease (e.g. identification of targets), to studying the relevance of animal findings in humans using human tissues/vessels obtained from patients undergoing liver transplantation (i.e. clinical relevance) and to develop and translate these to clinical setting (i.e. human studies).

In this project our group will investigate the therapeutic efficacy of human liver-specific adeno-associated viral vectors (AAV) carrying human angiotensin converting enzyme 2 (ACE2) gene in a humanized mouse model as a treatment for liver fibrosis. Humanized mice will be prepared by transplanting human hepatocytes into the liver of triple mutant FRG mice. Liver disease will then be induced in these mice to test the therapeutic efficacy of our human liver-specific AAV vectors such as LK03, NP40 and NP59, carrying human ACE2 gene. We have published the beneficial role of ACE2 in mouse models of chronic liver disease and a series of studies undertaken in this project will provide evidence whether our new human liver-specific vectors are tolerable and produce beneficial effects in a mouse liver repopulated with human liver cells. This information is vital for us before moving into human clinical trials.

These studies will establish human liver-specific ACE2 therapy is well tolerated and has powerful antifibrotic effects in humanized cirrhotic mice. Moreover, these studies are expected to identify the most effective hepatotropic capsid and confirm that ACE2 gene therapy is effective in human hepatocytes and provide evidence that it could be translated into clinical practice.

Novel therapies for hepatocellular carcinoma

Liver cancer (hepatocellular carcinoma or HCC) ranked the seventh most common cancer worldwide and is the second leading cause of cancer deaths worldwide. It is characterized with low detection rate for the curable stages, ineffective therapeutic options and high rate of relapse. Current ineffective therapeutic options warrant new research to develop novel therapies to treat this condition. Thus, there is an urgent need for research to improve our ability to diagnose, prevent, and treat this disease.

Our work will be expected to establish novel ways to target liver cancer cells without producing the toxic, off-target effects that are common to currently used chemotherapeutic drugs. We will use several pre-clinical and in vitro models of HCC to test the effects of a non-pathogenic adeno-associated viral (AAV) vector carrying proteins or peptides with anti-cancer properties or novel nano-particles called ‘Carbon-Dots’ (CDs) conjugated to those peptides.

These studies will establish human liver-specific ACE2 and peptide therapies has powerful anti-cancer effects in animal models of HCC. Moreover, these studies are expected to show that carbon-dot technology can be successfully used to target cancer cells without producing off-target effects, markedly contrasting current chemotherapeutics which produce many off-target effects. More importantly, the studies provide evidence that it could be translated into clinical practice.

Targeted therapy in diabetes and diabetic non-alcoholic fatty liver disease

Type 2 diabetes (T2D) is Australia’s most common chronic metabolic disease, and its prevalence is increasing world-wide, resulting in a growing burden of illness and greater healthcare costs. However, none of the current drugs used in T2D including metformin and pioglitazone help prevent progressive decline in β-cell function and survival over time. Thus, there remains a significant need to develop new treatments for diabetes which prevent the progressive decline in the function and survival of pancreatic β-cells (the cells that make insulin) which characterises this disease.

Our recent findings that ACE2 therapy produced a number of beneficial effects in the diabetic pancreas including increasing β-cell numbers and improving insulin production led us to design studies to discover potentially revolutionary treatment for T2D using well characterised diabetic models. Thus, our laboratory constructed a novel β-cell-targeted ACE2-AAV vector to selectively increase ACE2 expression in β-cells to prevent β-cell dysfunction and stimulate β-cell growth and insulin synthesis in T2D using diabetic db/db animal models (leptin-receptor deficient) that will develop hyperglycaemia at the age of 8 weeks and overt diabetes at 12 weeks of age.

Furthermore, approximately 70% of patients with T2D have non-alcoholic fatty liver disease (NAFLD) and it is known that diabetes accelerates NAFLD progression to liver cirrhosis and liver cancer. Indeed, NAFLD is now recognised as a leading cause of morbidity and mortality in diabetic patients. However, a safe and effective medical treatment has yet to be discovered for diabetic NAFLD. We will therefore further develop ACE2 gene therapy which targets both the liver and pancreas for the treatment diabetic NAFLD. Key aspects of this innovative technology with organ specific treatment are that it will have minimal or no adverse off-target effects and that its effects are prolonged (at least for 6 months) after a single administration, thus obviating the need for daily drug therapy.

The outcome of these studies is expected to provide that liver-specific ACE2 therapy has strong inhibitory effects on NAFLD/NASH progression and that the effects of diabetes which makes liver disease worse will be counteracted by pancreatic beta-cell-targeted ACE2 therapy. Moreover, we expect to show that beta cell-specific ACE2 therapy also has potential to treat type 1 diabetes by stimulating the growth of beta cells.

Targeted therapy in portal hypertension

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.

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.



  • Prof Ian Alexander, Children's Hospital Westmead, University of Sydney, Australia
  • A/Prof Anthony Zulli, School of Biomedical Sciences, Victoria University, Australia
  • Dr Harinda Rajapaksha, Oracle Australia
  • Prof Qin Li, Griffith University, Australia
  • Prof Micheal Bader, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
  • Prof Jonel Trebicka, University Clinic Frankfurt, Germany
  • Prof Keerthisiri Guruge, National Institute of Animal Health, Tsukuba, Japan
  • Prof Missaka Wijayagunawardena, Department of Animal Science, University of Peradeniya, Sri Lanka
  • Prof Matt Watt, Department of Physiology and Anatomy, The University of Melbourne, Australia
  • A/Prof Ross Laybutt, Westmead Institute of Medical Research, University of Sydney, Australia
  • A/Prof Sof Andrikopoulos, Australian Diabetes Society, Australia
  • A/Prof Leszek Lisowski, Children’s Medical Research Institute, Westmead, University of Sydney, Australia
  • Dr John Bruning, University of Adelaide, Australia
  • Prof Raymond Norton, Monash University, Australia


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

Research Outcomes

  • 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, Asadi K, Laybutt R, Andrikopoulous S, Alexander IE, Watt MJ, Angus PW, Herath CB. (2022) Angiotensin Converting Enzyme-2 Therapy Improves Liver Fibrosis and Glycemic Control in Diabetic Mice With Fatty Liver. Hepatology Communications May;6(5):1056-1072.
  • 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.
  • Bogahawaththa SB, Kodithuwakku SP, Wijesundera KK,   Siriweera EH, Jayasinghe L, Dissanayaka WL, Rajapakse J, Herath CB, Tsujita   T, Wijayagunawardane MPB. (2021). Anti-Fibrotic and Anti-Angiogenic   Activities of Osbeckia octandra Leaf Extracts in Thioacetamide-Induced   Experimental Liver Cirrhosis. Molecules Aug 10;26(16):4836.
  • 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.
  • Rajapaksha   IG, Gunarathne LS, Asadi K, Cunningham SC, Sharland A, Alexander IE, Angus   PW, Herath CB. (2019). Liver-targeted angiotensin converting enzyme 2   inhibits chronic biliary fibrosis in multiple drug-resistant gene-2knockout   mice. Hepatology Communications. Oct 10;3(12):1656-1673.
  • 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.
  • Casey S, Schierwagen R, Mak KY, Klein S, Uschner F,   Jansen C, Praktiknjo M, Meyer C, Thomas D, Herath CB, Jones R, Trebicka J,   Angus P. (2019). Activation of the alternate renin-angiotensin system   correlates with the clinical status in human cirrhosis and corrects post   liver transplantation. Journal of Clinical Medicine Mar 27;8(4).
  • Alamri AS, Brock JA, Herath CB, Rajapaksha IG, Angus   PW, Ivanusic JJ. Alamri, A.S. (2019). The Effects of   Diabetes and High-Fat Diet on Polymodal Nociceptor and Cold Thermoreceptor   Nerve Terminal Endings in the Corneal Epithelium. Investigative Ophthalmology & Visual Science Jan   2;60(1):209-217.
  • Fernando DH, Forbes JM, Angus PW,   Herath CB. Development and Progression of Non-Alcoholic Fatty Liver Disease:   The Role of Advanced Glycation End Products. (2019). REVIEW. International Journal of Molecular Science Oct   11;20(20).
  • Casey S, Herath CB, Rajapaksha IG, Jones R, Angus P.   (2018). Effects of angiotensin-(1-7) and angiotensin II on vascular tone in   human cirrhotic splanchnic vessels. Peptides 108:25-33.
  • Rajapaksha IG, Mak KY, Huang P, Burrell LM, Angus   PW, Herath CB. (2018). The small molecule drug diminazene aceturate inhibits   liver injury and biliary fibrosis in mice. Scientific   Reports Jul   5;8(1):10175.
  • Zhuang A, Yap FY, Bruce C, Leung C, Plan MR, Sullivan MA, Herath CB,   McCarthy D, Sourris KC, Kantharidis P, Coughlan MT, Febbraio MA, Hodson MP,   Watt MJ, Angus P, Schulz BL, Forbes JM.   (2018). Increased liver AGEs induce hepatic injury mediated through an OST48   pathway. Scientific Reports. Sep 25;7(1):12292.
  • Mak KY, Rajapaksha DIG, Angus PW, Herath CB. (2017). The   adeno-associated virus - A safe and effective vehicle for liver-specific gene   therapy of inherited and non-inherited diseases. REVIEW. Current Gene   Therapy. Mar 14 [Epub ahead of print].
  • Klein S, Herath CB, Schierwagen R, Grace JA,   Haltenhoj T, Uschner FE, Strassburg CP, Sauerbruch   T,   Walther T, Angus PW, Trebicka   J. (2015).   Hemodynamic effects of the non-peptide angiotensin-(1-7) agonist AVE0991 in   liver cirrhosis. PLoS One Sep   25;10(9):e0138732.
  • 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.
  • Yeung LW, Guruge KS, Taniyasu S, Yamashita N, Angus PW, Herath CB. (2013).   Profiles of perfluoroalkyl substances in the liver and serum of patients with   liver cancer and cirrhosis in Australia. Ecotoxicology and   Environmental Safety 96:139-46.
  • Herath CB, Mak KY, Burrell LM and Angus PW. (2013). Angiotensin-(1-7)   reduces the portal pressure response to angiotensin II and methoxamine via an   endothelial nitric oxide mediated pathway in cirrhotic rat liver. American Journal of Physiology 304(1):G99-108.
  • 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.

Research Projects

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For further information about this research, please contact Doctor Chandana Herath

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