Therapeutic Technologies

A Hallmark Research Initiative

The Therapeutic Technologies Hallmark Research Initiative was announced in 2015 with funding from the Deputy Vice-Chancellor Research for three years. Professor Alastair Stewart and Dr Susan Northfield, former chair and Academic Convenor respectively, remain involved with an active community of researchers in this field at the University.

This Initiative was vital to pave the way for a new ARC-funded Industrial Transformation Training Centre (ITTC) focused on Personalised Therapeutics Technologies. This ITTC will foster a vibrant, sustainable, growing industry of highly skilled researchers using organ-on-a-chip and bioprinting technologies that will support improved selection of therapeutics for investment in clinical trials.

Context

The Therapeutic Technologies Hallmark Research Initiative was established to bring together a unique, critical mass of highly experienced scientists from across a range of disciplines (including pharmacology,engineering, physics, chemistry) and faculties to engage with industry to develop mechanistic and discovery studies requiring phenotypic screening in 3D chronic disease models. In addition to the quality research supported by the Initiative through generous seed-funding grants, numerous seminars, symposia and workshops for university staff and students were also offered.

The Initiative has handed over an established portfolio of connections and activities to the new Centre for Personalised Therapeutics Technologies, which is maintaining and growing the local community of researchers in the field.

Approach

Activities of the Therapeutic Technologies Hallmark Research Initiative focused on new applications of mechanopharmacology and organ-on-a-chip technology to transform drug screening processes. The Initiative selected three research themes as areas of focus:

Cell/Tissue/Organ-on-a-chip drug screening technology - Drug Evaluation
Cellular biomechanics - Mechanopharmacology
Stem cells and disease modelling.

Key outcomes

Establishment of our ARC-funded Centre for Personalised Therapeutics Technologies
Annual science communication workshop for research students
Development of an extensive network of researchers in the therapeutic technologies field
Engagement with industry partners.

Therapeutic Technologies HRI Seed Funding Awarded

2018
Modelling retinal inflammation in Alzheimer’s disease using iPSC-derived RPE and microglia
- Lead investigator: Grace Lidgerwood. Co-investigators: Alice Pébay, Rosie Watson
- This project aims to assess the interaction and response of retinal cells with immune cells in a model of Alzheimer’s disease (AD), using patient iPSC-derived retinal cells and microglia. It has real potential to develop a new and accurate model to functionally assess AD pathology, and a predictive model.
Quantitative proteomic analysis of drug response in metastatic colorectal cancer
- Lead investigator: Jonathan Mangum. Co-investigators: Frédéric Hollande
- This project aims to address the current limitations in colorectal cancer (CRC) by using tumour organoids, which are hypothesised to represent a great model to combine molecular and phenotypic analyses of CRC liver metastases.
Patient-derived liver cancer organoids to personalise anti-cancer treatment
Lead investigator: Dale Christiansen.  Co-investigators: Elizabeth Vincan, Joseph Torresi, Manh Bang Tran
In this project researchers adopt organoid technology to establish a high-throughput platform to test their sensitivity to agents currently used to treat liver cancer, eradicate hepatitis B virus, and new emerging therapies, both in isolation and in combination. Using patient-derived organoids, they aim to develop personalised therapies for the patient.
Molecular tension probes to measure cell migration – a proof of concept study
Lead investigators: Susan Northfield and Daniel Heath.  Co-investigators: Brian Gao, John Karas
In this project researchers aim to develop a mechanical biosensor that can be applied in mechanopharmacology research to measure mechanical stimulation resulting from cell migration. The novelty of this work is the application of the biosensors to assays with synthetic extracellular matrices of varying ‘stiffness’ allowing us to measure the impact of stiffness on mechanical migration of cells.
Development of Biocompatible Hydrogel with Tuneable Stiffness for 3D Cell/Tissue Culture
Lead investigator: Bryan Gao.  Co-investigators: Susan Northfield, Alastair Stewart, Daniel Heath, Meina Li
This project aims to establish a workflow for synthesis and characterization of polyethylene glycol (PEG)-based biomimicry hydrogel for long-term culturing of cells and spheroids/organoids. Collectively, we will be able to manipulate both physical and biochemical parameters of the 3D culture environment to more closely recreate the physiological conditions.
Biodegradable and biocompatible magnetic materials for mechanotransduction in vitro
Lead investigator: Andrea O’Connor.  Co-investigators: David Simpson, Javad Jafari
This project will develop methods to synthesise and characterise advanced magnetic nanobiomaterials to allow more precise control of the forces applied to cell and tissue constructs in vitro. It will have benefits in creating systems that enable spatial and temporal control of both active and passive mechanical stimuli on cells, which can be applied for improved mechanotransduction in tissue engineering and in vitro drug screening.
2017
Characterising pluripotent stem cell reprogramming using fluorescent barcoding
- Lead investigator: Frédéric Hollande. Co-investigators: Christine Wells, Alice Pébay, Davide Ferrari
- Induced pluripotent stem cells (iPSCs) represent an ideal model to investigate the mechanisms of self-renewal and differentiation during human embryonic development. This project combines an innovative fluorescent barcoding technology with systems biology and mathematical modelling to monitor, identify and analyse the molecular characteristics of cells that fail or complete the reprogramming process.
Design of an air-liquid-interface microfluidic chip with an array of electrode
- Lead investigator: Mirella Dottori. Co-investigators: Sophie Payne, Owen Burns, Tania Kameneva
- Transepithelial electrical resistance (TEER) is a commonly accepted non-invasive technique to measure electrical resistance across a cellular layer. This project incorporates TEER measurement into an on-a-chip microfluidic platform for continuous monitoring of cell mechanical properties and cell integrity in response to drugs.
Using stem cell models to investigate mitochondrial protein transport in disease
Lead investigator: Diana Stojanovski. Co-investigators: Ann Frazier, David Elliott, David Thorburn
Mitochondria are “power stations” that provide our cells with energy in the form of ATP, but also play important roles in metabolism, oxidative stress, calcium homeostasis, cell signalling and death. This project involves generating human stem cell (hESC) knock out lines for a panel of mitochondrial disease genes. These stem cells will be differentiated to disease relevant cell types for further investigation, which will provide us with a powerful opportunity to dissect the pathomechanisms of specific mitochondrial diseases in a tissue specific manner.
A role for C. elegans in high-throughput drug discovery: Bridging the innovation gap
Lead investigator: Raymond Dagastine. Co-investigators: Simon James, Gawain McColl
The stubborn resistance of Alzheimer’s disease (AD) to effective therapeutic intervention, coupled with the increasing costs of drug development, demand new & cost-effective technologies better able to identify which of the “hits” emerging from discovery pipelines will show efficacy in the clinic. This project involves developing an automated microfluidic platform to undertake both high-throughput and high-resolution imaging.
2016
Microfluidics device for automated preparation and maintenance of air-liquid interface epithelial cell culture
- Lead investigator: Dr Christine Keenan. Co-investigators: YuXiu (Connie) Xia, Vijay Rajagopal
- The cells that line our lungs (epithelial cells) sit at the interface between the air we breathe and our blood supply carrying vital nutrients for cellular health. Recapitulating this environment in the laboratory means we can grow cells that physically resemble the airway surface. In this project, we are developing a microfluidics device to automate air-liquid interface culture of epithelial cells., which will allow live measurements of cellular function and will comprise a transformative addition to the field of organ-on-a-chip technology.
A diagnostic device for studying rare cell types in patient samples for laboratory and clinical use
- Lead investigator: Dr Daniel Heath. Co-investigators: Bill Kalionis, Shaun Brennecke
- Rare cells such as stem cells or metastatic tumour cells are critically important to human health. However, the rarity of these cells makes them difficult to isolate and study. This project involves developing a new cell culture platform that will enable these rare cells to be isolated and cultured individually in order to assess their true prevalence in patient samples as well as determining the heterogeneity within the cell population. This cell culture platform will enable unprecedented insight into the biology of these cells and has the potential to be used in disease diagnostics.
Controlling the ‘Master’: Generating more relevant models to facilitate discovery of novel mast cell regulators
Lead investigator: Dr Graham Mackay.  Co-investigators:  YuXiu (Connie) Xia, Paul McMillan
Mast cells are found everywhere in the body and whilst their pariah status in allergic disease is well known, there is increasing evidence that these cells can play both deleterious and protective roles in many other diseases and are thus truly ‘master’ cells. In this project we identify extracellular matrix compositions that permits optimal adherence of human mast cells and examine the effects of these matrices on mast cell phenotype and activation.
Identifying novel inhibitors using an FDA-approved drug screening library on a drosophila brain tumor model
Lead investigator: Dr Rodney Luwor.  Co-investigators: Leonie Quinn
Surgery to remove brain cancer tumours in almost all cases leaves residual tumour cells that continue to divide uncontrollably, leading to tumour recurrence and patient mortality. There is an urgent need to discover novel therapeutic agents that will prolong the survival times of patients with glioblastoma. This project involves screening a large number of potential FDA-approved agents for their efficacy in established Drosophila brain tumour models to identify novel agents that can inhibit brain tumour proliferation and invasion.
Modelling retinoblastoma using human induced pluripotent stem cells (iPSCs)
Lead investigator: Dr Raymond Wong.  Co-investigators: Sandy Hung, Sandra Staffieri, Alice Pébay, Alex Hewitt, David Mackey
Retinoblastoma (RB) is the most common malignant tumour of the eye in children caused by mutations in the RB1 gene. This project involves using RB patient-derived iPSCs with known mutations, to model this disease. Studies from this project will build a better understanding for RB disease with the ultimate aim to drive advancements in better treatment for patients.