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.
- 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
- Prof Ian Alexander, Children's Hospital 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.
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.
- 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.
- 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.
For further information about this research, please contact the research group leader.
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