MRFF funding boosts incurable diseases research

Monash University welcomes $2.44 million in funding from the Medical Research Future Fund (MRFF) Stem Cell Therapies Mission.

Congratulations to the four grant recipients.

These research projects will help with the development of new practical treatments for Australians with debilitating conditions including fatty liver disease, epilepsy, muscle wasting disorders and vasculitis.

Using muscle stem cells to treat muscle injury and wasting disorders

Professor Peter Currie from the Australia Regenerative Medicine Institute (ARMI), Associate Professor Milkael Martino EMBLAustralia (ARMI),  and Professor Laurence Meagher from Monash Institute of Medical Engineering.

Muscular dystrophies and myopathies have been reported to have one of the highest burdens of disease in Australia, with the Disability Adjusted Life Years Lost being estimated to be higher than that of cancer and multiple sclerosis. In 2005, the financial cost for the treatment and loss of productivity associated with muscular dystrophy in Australia was estimated at $435 million per year. There are currently no treatments for any of this diverse group of disorders.

Furthermore, sarcopenia, an inevitable muscle wasting disease of the elderly, looms as a major health issue in our ageing population and is considered a major contributor to morbidity and poor life quality in the elderly. Cancer induced muscle wasting or cachexia is also a significant cancer comorbidity. An ability to regulate muscle stem cell proliferation and repair in vivo would provide a mechanism of therapeutic intervention for all these disorders.

This project builds on work that has defined the signals that direct muscle stem cell proliferation in vivo. Components of the cellular immune system, in particular the macrophage, are emerging as key regulators of this process. The overall direction for this project is to develop directed therapies from the novel macrophage-derived muscle cytokine, NAMPT that  have been identified.  Using the distinct skill sets within the respective research teams and defined project milestones, the team will build a specific set of NAMPT-based therapeutics that stimulate muscle stem cell mediated regeneration and enhance muscle stem cell transplantation engraftment in a variety of muscle injury and disease contexts.

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 Disease Monash Health at the School of Clinical Sciences at Monash Health.

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 personalised treatments for epilepsy

Professor Patrick Kwan, Department of Neuroscience at Central Clinical School.

Epilepsy is a severe neurological disease which affects over 70 million people globally. Despite a concerted effort to identify new anti-seizure medications (ASMs) over the last 25 years, epilepsy remains uncontrolled in 30% of individuals, a condition known as drug-resistant epilepsy. This project will take stem cells from both healthy individuals and those with drug-resistant epilepsy, and grow their stem cells in vitro into neurons. Researchers will test the ability of a library of drugs to suppress the abnormal activities of these neurons. The process will enable rapid assessment of new effective drugs that target drug-resistant epilepsy at a speed and scale not possible with conventional animal methods.

New treatments for fatty liver disease

Associate Professor Rebecca Lim, Obstetrics & Gynaecology at the School of Clinical Sciences at Monash Health.

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.