Targeted ACE2 gene therapy in liver fibrosis

Project Details

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.



  • Prof Ian Alexander, Children's Hospital Westmead, University of Sydney, Australia
  • A/Prof Leszek Lisowski, Children’s Medical Research Institute, Westmead, University of Sydney, Australia


  • 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

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.

Research Publications

Selected Publications:

  • 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.
  • 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).
  • 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.
  • 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].
  • 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.
  • 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.

Research Group

Hepatology and Gastroenterology Research Group

Key Contact

For further information about this research, please contact the research group leader.

Department / Centre


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