Translational Kick-Start Award

Principal Investigator: Dr Wayne Ayre
School of Dentistry

This project will identify a novel micro/nano-scale pattern on metal implant surfaces that prevents infection and encourages bone healing in order to prolong the lifespan of joint replacements and dental implants.  Approximately 7% of hip and knee replacements failed in England and Wales in 2015, with the main cause being infection and loosening of the implant. Similar statistics and mechanisms of failure have also been reported for dental implants. Recent research has found that metal surfaces with structures 100-times smaller than the width of a human hair can kill bacteria as well as encourage bone to grow.

This project proposes to apply a surface treatment developed by an industrial partner to create a micro/nano-scale pattern on 3D printed metals, which will be screened for antibacterial properties against bacteria from infected dental and orthopaedic implants at the School of Dentistry, Cardiff University. This pattern will also be assessed for toxicity and its potential to encourage bone growth.  The development of more effective implant surfaces has the potential to improve patient quality of life by reducing the need for multiple surgeries and cut costs significantly for both patients and the NHS.

Principal Investigator: Dr Youcef Mehellou
School of Pharmacy and Pharmaceutical Sciences

Modulating the immune system's response to fight and kill tumours is emerging as a powerful approach in the fight against cancer. Recent research has identified a group of the immune system's cells that act as sensors to detect tumours, leading to the activation of the immune system. This eventually results in the killing of cancer cells and tumours. Drugs designed to activate this subgroup of immune cells could therefore be useful in treating cancer.

In this project, we aim to design new drugs (synthetic molecules) that activate the immune system to specifically eradicate cancer cells and tumours. A particular focus of the work will be on developing these compounds as new, effective and safe treatments for bladder cancer, the 5th most common· cancer in the UK with a 10-year survival rate of less than 50% with current treatments. Ultimately, these synthetic molecules will represent an exciting new dimension in the treatment of bladder cancer, which will improve the treatment outcomes of patients with this serious disease.

Principal Investigator: Dr Richard Stanton
School of Medicine

Human cytomegalovirus is the biggest infectious cause of congenital malformation worldwide. In the UK alone 1,000 babies are born every year with lifelong disability resulting from infection, in the USA over 40,000 infected babies are born every year. The cost of caring for these individuals exceeds $300,000 per child per year. The only available treatment are antiviral drugs, however these can be toxic and therefore cannot be used in many patients. As a result, there is a desperate need for better treatments.

A cell type called Natural Killer (NK) cells are crucial to controlling HCMV infection and disease, but they only kill efficiently when they bind to antibodies on the surface of infected cells. If we can generate antibodies that bind to infected cells, but not uninfected ones, these could be given to infected patients, then their own NK cells will become able to kill the infection. We have identified suitable viral proteins that are found only on the surface of infected cells. In collaboration with a company that specializes in generating therapeutic monoclonal antibodies, we will now generate and test antibodies that can bind these proteins. Such antibodies have the potential to be a highly effective antiviral therapy.

Principal Investigator: Dr Marcella Bassetto
School of Pharmacy and Pharmaceutical Sciences

Norovirus, also called the “winter vomiting bug” because outbreaks often occur in winter, is the most common stomach bug around the world and in the UK, causing large epidemics of acute gastroenteritis. Infection with this virus causes 200,000 deaths in children in developing countries every year, and it affects nearly one million British people annually, causing watery diarrhoea, projectile vomiting and flu-like symptoms. Norovirus is a particularly contagious bug, which can live on surfaces for up to five days and is transmitted by contact with contaminated objects, water and food, representing a major cause for the closure of hospitals, wards and hotels.

Unfortunately, specific treatments or vaccines are not available, therefore the development of safe and selective antivirals against this virus is urgently required. In our research group, we have found two potential drugs that, blocking a viral protein, can kill the virus stopping its negative effects.

In this study, using different computer techniques, we aim to design and prepare more potent antivirals changing the chemical structure of our two drugs. These novel substances will be tested in specific antiviral assays to evaluate their ability to kill the virus and their potential to become a viable treatment against this infection.

Principal Investigator: Dr Ryan Moseley
School of Dentistry

Normal healing in skin occurs through many different stages, culminating in scar formation and wound closure. However, excessive or abnormal scarring can occur during clinical situations, such as keloid scars, burn injuries or surgery. Indeed, ≈100 million patients annually develop scars in the developed world, following surgery alone. As clinicians often find these scars difficult to treat, they cause significant pain and disability in patients, dramatically affecting patients’ physical and psychological quality of life. Consequently, such scars pose major social, economic and clinical challenges to Healthcare Services worldwide, exacerbated by existing therapies being unsatisfactory as scar treatments. As no effective therapies currently exist, there is a significant need to develop improved treatments for excessive/abnormal scarring in skin.

We have developed a naturally-occurring, chemical compound (ingenol mebutate), which possesses potent anti-cancer and anti-scarring properties in skin. This compound has significant beneficial effects on fibroblast and myofibroblast cells responsible for scar formation in normal skin, by encouraging scar breakdown. We will now examine whether ingenol mebutate has similar effects against fibroblasts/myofibroblasts from keloid scars, which clinicians find extremely difficult to treat. By confirming ingenol mebutate effectiveness against keloid scars, we can develop this compound as a treatment for excessive/abnormal scarring in patients.

Principal Investigator: Dr Julian Forton
School of Medicine

Bacterial lung infection is the major cause of death in people with CF. Early diagnosis of infections is vital to prevent progressive lung damage. While conventional bacterial culture from CF sputum is currently used to diagnose pathogens, it has multiple limitations. It cannot account for the abundance of multiple organisms found in CF sputum and misses difficult to identify bacteria. Children with CF often cannot produce sputum so cough swabs (inaccurate and fail to sample deep in the lung) or surgical lavage procedures (invasive, expensive and risk associated) are used.

We will assess a new sampling method called induced sputum and perform a systematic comparison of conventional and molecular (DNA) approaches to diagnose CF infection. DNA diagnostics are more accurate compared to growth-based microbiology and can detect all organisms in a sample, but they are not used routinely in clinic. A clinical trial evaluating induced sputum sampling for CF children is underway, and we will compare DNA-diagnostics to standard microbiology carried out by Public Health Wales (PHW). We aim to translate both induced sputum and DNA-testing into routine practice, and enhance healthcare for people with CF.

Principal Investigator: Dr Alan Parker
School of Medicine

Ovarian cancer can spread across the lining of the abdominal cavity. When this happens the cancer becomes difficult to treat as surgery to remove deposits is usually impossible. Scientists have developed a new technology (termed PIPAC) to treat cancer that has reached this advanced stage. It enables surgeons to spray aerosolised chemotherapy into the abdominal cavity of patients during 'keyhole' surgery, a technique that has demonstrated efficacy in early clinical studies. In Cardiff, we are developing sophisticated virotherapies modified to selectively infect and kill cancer cells. In this process, infected cells produce more therapeutic virus that can be released and spread to surrounding tumour cells, repeating the process and amplifying the therapy at the point of need. Virotherapies can be additionally modified so that they produce large quantities of anti-cancer agents, such as therapeutic antibodies.

A major barrier to 'virotherapy' is that the body's immune system rapidly recognises and eliminates therapeutic virus. The new device may represent a potential solution, enabling the viruses to reach cancer cells before they are inactivated by the host immune system. The first step is a series of in-vitro experiments to assess whether the viruses can survive delivery through the device and remain biologically active.

Principle Investigator: Dr Elaine Ferguson 
School of Dentistry

Bacterial infections affect more than 80% of patients receiving chemotherapy for acute leukaemia, and about one third of them will die. Antibiotics are used to prevent infections during chemotherapy treatment. Widespread misuse, however, has resulted in increasing antibiotic resistance, meaning that antibiotics are becoming ineffective.

Recently, researchers have shown in the laboratory that the antibiotic, colistin, can kill not only bacteria, but also certain cancer cells. Unfortunately, colistin has serious side effects, especially causing damage to the kidneys. Using materials extracted from corn, we have developed a way of stopping colistin getting into and damaging vital organs. This protective coat also shields the drug from being broken down into inactive pieces and keeps it in the bloodstream for longer. This approach effectively reduces the side effects of conventional drugs, while sustained antibiotic exposure may help reduce antibiotic resistance.

Having previously shown that our coated colistin retains its ability to kill bacteria, this project will focus on the growth and survival of a variety of normal and cancerous blood cells in the presence of our modified antibiotic. This work combines, for the first time, expertise from three research groups from three Schools within Cardiff University’s College of Biomedical and Life Sciences.

Principle Investigator: Dr Richard Stanton 
School of Medicine

Human cytomegalovirus (HCMV) is the biggest infectious cause of congenital malformation worldwide. In the UK alone 1,000 babies are born every year with lifelong disability resulting from infection, in the USA over 40,000 infected babies are born every year. The cost of caring for these individuals exceeds $300,000 per child per year. The only available treatment are antiviral drugs, however these can be toxic and therefore cannot be used in many patients. As a result, there is a desperate need for better treatments.

A cell type called Natural Killer (NK) cells are crucial to controlling HCMV infection and disease, but they only kill efficiently when they bind to antibodies on the surface of infected cells. If we can generate antibodies that bind to infected cells, but not uninfected ones, these could be given to infected patients, then their own NK cells will become able to kill the infection. We have identified suitable viral proteins that are found only on the surface of infected cells. We now wish to collaborate with an industry partner to generate such antibodies using a technique called phage panning. These antibodies have the potential to be a highly effective antiviral therapy.

Principle Investigator: Professor Andrew Sewell 
School of Medicine

Vaccination is estimated to have saved billions of human lives and ranks amongst the very highest achievements of mankind. While vaccines against killer diseases such as smallpox, polio and diphtheria have been largely successful, diseases like TB, malaria and the potential risk of bird flu or other emerging infectious diseases still rank amongst the major threats to humanity. In addition, there are no vaccines for livestock diseases such as African swine fever and Foot and Mouth disease and the preferred current disease management option is an industry standstill and extended culling/incineration.

The Cardiff T-cell group have recently developed the world’s first synthetic non-biologic vaccine. This compound protected humanized mice from lethal challenge with influenza virus and could induce immunity when given orally. This work opens up the possibility of pill-based vaccines. Here, we aim to apply similar approaches to cancer vaccination in humans. Initial studies in the laboratory show that we can induce good immunity to cancer using this approach. We will also extend our infection studies by building peptide and non-peptide vaccines for swine flu in pigs. The pig represents an ideal model for these studies and will provide a good stepping stone towards vaccine applications in human.

Principle Investigator: Professor Ian Weeks 
School of Medicine

This project aims to develop an innovative stratification method that will allow early identification of patients whose wounds will fail to heal normally over time. Chronic wounds can take several months to years to heal. This can be debilitating for patients, leading to reduced quality of life through severe emotional/physical stress, reduced mobility and limited productivity. The estimated cost of wound treatment per annum for chronic wounds is £2-3 billion (3.5% of the NHS spend).

Effective stratification of patients would permit the targeting of specialist treatments to patients that will benefit most. The objective of this project is to develop non-invasive diagnostic tests based on the molecular profile of wound fluid which facilitate stratification of patients. The objectives are to: profile the micro RNAs (miR) biomarkers extracted from wound fluid and identify those that can distinguish between wounds that are healing and those requiring intervention; to optimise a companion diagnostic technology based on chemiluminescent detection to measure and quantify the specific miRs as this technology has potential to provide a quicker, cheaper and more robust method and to test a novel method of storing wound fluid at room temperature on patient samples.This research will be a critical step in the development of a non-invasive test to stratify wounds into ‘healing’ or ‘non-healing’ groups early in patient assessment.

Principle Investigator: Dr Marcella Bassetto
School of Pharmacy and Pharmaceutical Sciences

Retinitis pigmentosa (RP) and Leber’s congenital amaurosis (LCA) are severe blinding diseases that can be caused by aggregation of a protein called opsin, whose proper function enables vision. Retinitis pigmentosa is a degenerative congenital eye disease that affects 1 in 4000 people and causes severe vision impairment in all age groups. Leber’s congenital amaurosis is the most severe retinal pathology in infants and it causes blindness before one year of age, affecting the 20% of children in schools for the blind. A cure for these conditions is currently not available.

Opsin aggregation is prevented in physiological conditions by 11-cis-retinal, an endogenous substance that stabilises opsin structure by binding to it. Using computer-aided techniques, this study aims to optimise novel drugs that mimic the function of 11-cis-retinal and prevent opsin aggregation, providing the basis for a cure against RP and LCA. Different new small molecules have been identified in our group, which show the potential to help opsin stability by preventing aggregation. By inserting chemical modifications on the structures of these drugs, we aim to prepare more potent molecules, which could potentially become a viable treatment for blinding diseases caused by opsin aggregation.