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.
- 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)
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.
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.