L-R: Prof Stephen Holdsworth, Dr Dragana Odobasic, Dr Poh-Yi Gan, Dr Kim O’Sullivan and A/Prof Rebecca Lim |
These research projects will help with the development of new practical treatments for fatty liver disease and vasculitis.
Using stem cells to treat an autoimmune disease that causes inflammation of blood vessels
Professor Stephen Holdsworth, Dr Dragana Odobasic, Dr Poh Yi Gan and Dr Kim O’Sullivan from the Centre for Inflammatory Diseases
Human Amniotic Epithelial Stem Cells as Novel Treatment for Autoimmune Vasculitis
Vasculitis caused by autoimmunity to myeloperoxidase (MPO) is a serious disease affecting small blood vessels, particularly in the kidney. It is a common cause of morbidity and mortality in Australia and worldwide. Current treatments, which consist of broad immunosuppressants, are only partially effective and produce many serious side effects, mainly infections and cancer, from which most patients die. Therefore, there is an urgent need for safer, effective therapies. Human amniotic epithelial stem cells (hAECs) represent a novel, safe and affordable therapeutic option for anti-MPO vasculitis. This is due to their immunosuppressive capacity and anti-microbial/cancer properties, as well as low immunogenicity, and high yields being isolated from an abundant source (placenta) in an ethical and speedy manner. Feasibility and safety of hAECs has already been demonstrated in several phase I trials in various inflammatory conditions at Monash Health. However, their therapeutic efficacy has never been tested in anti-MPO vasculitis.
Using relevant pre-clinical models and patients’ cells, as well as humanized mice, these proof-of-concept studies will test the therapeutic benefit of hAECs in anti-MPO vasculitis. They will identify hAECs as an appealing new therapy for this condition and provide the critical, initial stepping stones which will pave the way for their progress into a clinical trial at our precinct. This therapy has the potential to change clinical practise in anti-MPO vasculitis, provide immense benefit to patients by decreasing their risk of death and complications from serious side effects, and reduce the overall, long-term treatment costs associated with this devastating disease.
New treatments for fatty liver disease
Associate Professor Rebecca Lim, Department of Obstetrics & Gynaecology
Liver disease is responsible for a quarter of all organ transplants in Australia and represents a significant healthcare burden. The most common liver disease is non-alcoholic fatty liver disease (NAFLD), which itself is benign but in association with chronic inflammation (non-alcoholic steatohepatitis; NASH), can progress to cirrhosis and liver cancer. By 2020, NASH will have replaced hepatitis C as the number one reason for liver transplantation and there is no cure for NAFLD/NASH. Alternatives are urgently needed by patients with end stage NAFLD/NASH who are not candidates for liver transplantation or for whom no donor is available.
The team aims to develop a multivalent therapeutic for this complex disease based on extracellular vesicles (EV) released by amniotic epithelial cells (hAEC) that addresses fibrosis, apoptosis, oxidative stress and endogenous repair. They provide preliminary evidence that EVs released by hAECs are anti-fibrotic and support the differentiation of liver progenitor cells, promoting recovery of liver function in chronic liver disease. We have pilot data indicating that hAECs cultured on softer 3D microcarriers can significantly increase EV yield as well as biological potency compared to culture on traditional 2D tissue culture plastic.
We thus hypothesise that it is possible to tune the potency of hAEC-EVs by manipulating mechanotransduction through culture on softer microcarriers that are specifically functionalised to improve anti-fibrotic effects for NAFLD/NASH.
In this application, the team aims to:
(i) Develop a novel method of hAEC-EV manufacturing for optimal EV yield and potency through the manipulation of microcarrier stiffness and functionalisation and;
(ii) Evaluate an oral formulation of hAEC-EVs against competitor treatments in preclinical mouse model of NASH.
The team brings our combined expertise of hAEC and EV biology, materials science, NAFLD/NASH management and clinical translation to address this urgent unmet medical need.
For more information see Monash story.
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