Confidence for Translation (C4T) Awardees 2022

by | Jan 23, 2023 | Case studies, News | 0 comments

In 2022, Translation Mancheste run the first Translation Manchester Accelerator Awards (TMAA) call, bringing together funding from the Wellcome Translational Partnership Award (TPA) and the UKRI MRC Impact Accelerator Account (2022-25).

 

This funding call included two schemes; Confidence for Translation (C4T) and Access to Expertise (A2E). The call was extremely competitive with a great number of high quality proposals received for consideration. After thorough peer review the following proposals were funded:

 

The following projects were funded through the Wellcome TPA:

Helen Hawley-Hague
Exploring the usability and acceptability of a virtual reality training programme to increase awareness of falls prevention and management

Madhvi Menon
Harnessing the nasal proteome for early detection of lung cancer

Tom Jowitt
Tools for stem cell biomarker identification

The following projects were funded through the Institutional UKRI MRC Impact Accelerator Account 2022-25

Paul Kasher
Angiotensin-converting enzyme inhibitors as a neuroprotective strategy for intracerebral haemorrhage: a proof of principle in vivo study

Sarah Herrick
Novel hydrogel-based drug delivery strategies to prevent surgical adhesions

Steven Rogers
Developing AI based computational modelling software for the prediction of cardiovascular events in high-risk patients.

Robert Wykes
In vivo evaluation of the efficacy of a novel anti-epileptic drug and gene therapy strategy to suppress spontaneous seizures.

Steven Taylor
Re-purposing cabazitaxel to overcome drug pump-mediated taxane resistance in high-grade serious ovarian cancer

Shruti Garg
Optimizing non-invasive brain stimulation for working memory difficulties in Neurofibromatosis

These studies join our strong portfolio of translational research projects, spanning across the full translational pathway, which we are currently supporting in order to facilitate their journey towards patient benefit.

 

A lay summary for each project can be found below:

 

Rob Wykes

Controlling epilepsy using a novel gene therapy strategy based on regulation of neuronal firing-rate homeostasis.

Epilepsy is a common neurological disorder affecting 1-2% of the population. Current antiepileptic drugs (AEDs) are effective for two-thirds of patients; the remainder do not respond to drug-intervention. As such there is a large unmet clinical need for this group of drug-resistant patients. Neurons, in all animals, utilise homeostatic mechanisms to maintain stability of activity, an optimal balance between brain excitability and inhibition. We propose that seizures occur because of compromised homeostatic mechanisms allowing run away excitation. Using the fruit fly as a model system we have identified a protein whose function is central to neuronal firing-rate homeostasis: allowing neurons to maintain appropriate levels of action potential firing. In the same model we could reduce seizures by upregulating the expression of this protein.

Experimental treatment options for drug-resistant epilepsy include gene therapy strategies. Gene therapy is based on the rational design of molecular tools to achieve brain region – and cell-specific modification of neuronal and circuit excitability. Additionally, localised treatment avoids the side-effects of global delivery of AEDs, and long-lasting efficacy can be achieved following a single administration. In this Confidence for Translation proposal we will investigate in preclinical models of chronic drug-resistant epilepsy whether a gene therapy approach designed to control neuronal firing-rate homeostasis is capable of reducing spontaneous seizures and therefore show efficacy as a novel anti-epilepsy treatment. This will be achieved using a state-of-the-art video telemetry system to determine seizure frequency and severity suppression following administration of our novel gene therapy and will be compared to a previously published gene therapy strategy which works through a different mechanism to establish whether our approach demonstrates superiority.

Helen Hawley-Hague

Exploring the usability and acceptability of a virtual reality training programme to increase awareness of falls prevention and management

Falls are a significant issue in the care home sector, with residents three times more likely to fall than in the community. Residents are at higher risk of falling due to their increased complex health and care needs and often have multiple factors which can cause them to fall.

Due to the environment in care homes and the fact that quite a lot of older adults within care homes have complex issues, falls prevention and management needs to be mostly led by the care home staff rather than targeting the individual residents. Evidence suggests barriers to implementation of falls prevention interventions in care homes include a lack of knowledge and access to training for staff. There are difficulties in care homes accessing training and a lack of evidence-based falls prevention programmes created specifically for the care home environment. There are also issues with staff engagement. It is apparent that care staff need more effective, engaging training to improve their knowledge and skills.

Initial work by the research team suggests that care homes had inconsistent access to falls awareness training, with some care homes having none, despite demand. Previous research conducted across 10 care homes suggested thatthe most effective and engaging training is practical, interactive, with skills that easily transfer to the workplace and residents. We propose a virtual reality based interactive falls training programme that managers and care home staff can engage with whenever suits them. We have completed initial research to co-develop a basic version with care home managers and staff. This project will build on that work using more co-development and research (workshops, interviews and interactive observations) with two care homes and produce a full version of the training that can be fully tested within care home environments. We hope that this product will lead to better falls management and prevention and therefore fewer falls, hospital admissions and better quality of life for residents.

Madhvi Menon

A new nasal swab test for lung cancer detection

Lung cancer is responsible for most cancer related deaths in the world. This is because early lung cancer causes no symptoms to prompt people to seek medical attention. Symptoms only occur in late-stage disease, at which time treatment options are very limited and in many cases death occurs within a few months of diagnosis. CT scans can detect early lung cancer and have been shown to prevent cancer related deaths when targeted to people with a significant smoking exposure. However, delivering widespread CT scans across the country is going to be logistically challenging and costly. We reasoned that a simple, cost-effective test that is specific enough to identify people who don’t have lung cancer (and don’t need a CT scan) could have benefit in reducing the number of CT scans that need to be performed. We previously took nasal swabs from people attending a CT screening pilot and have identified a signal that is only present in the patients who have lung cancer. In this study we are going to confirm that this signal is unique to lung cancer by testing more people. This will involve taking nasal swabs from patients newly diagnosed with lung cancer and controls. We will also determine whether our signal can still be detected on the swabs after they have been through the postal service. If this is possible, it opens the opportunity for home self-testing, which could broaden the reach of lung cancer screening, including underserved communities who are less likely to attend healthcare appointments. We will use the results of this study to plan a clinical trial to investigate whether our signal can be converted into a new test for lung cancer.

Paul Kasher

Angiotensin-converting enzyme inhibitors as a neuroprotective strategy for intracerebral haemorrhage: a proof of principle in vivo study.

Investigators: Dr Paul Kasher (lead), Prof. Stuart Allan, Dr Adrian Parry-Jones, Dr Ben Dickie.

Intracerebral haemorrhage (ICH) is a type of stroke caused by bursting of blood vessels within the brain. ICH is a leading cause of death and disability worldwide and yet we do not have any specific medications to treat the brain injury in patients after the bleed. Therefore, we need to increase our efforts for identifying and testing new medicines for ICH.

Zebrafish are an increasingly popular tool for studying human diseases, and we have developed them as a system for studying ICH. Young zebrafish are small and produced in large numbers meaning we can use them to easily test thousands of potential medicines for ICH. Furthermore, young zebrafish are see-through meaning we can use microscopes to watch how brain cells respond to blood. We have performed a large drug screen and have shown that a type of blood pressure lowering drug, known as an angiotensin-converting enzyme inhibitor (ACE-I), is able to block brain injury after ICH in young zebrafish. ACE-Is are commonly given to people to control blood pressure, including ICH patients. As such, we have analysed existing clinical data and shown that patients who received ACE-Is after their ICH have much better outcomes compared to patients not treated with ACE-Is. Therefore, we think that ACE-Is given for the first time quickly after ICH might be a promising new way to protect patient brains. Additionally, we also think that the way the ACE-Is work in this scenario is different to their normal role of controlling blood pressure, and they are likely protecting brain cells in a different way. As we only have evidence from zebrafish and retrospective clinical trial data, we need to do another animal study to directly show that ACE-Is can work in a mammalian model.

Importantly, we have been awarded funding by Translation Manchester to test ACE-Is in a mouse model of ICH. Based on the zebrafish and patient analysis, we will treat mice quickly after ICH with an ACE-I and then test whether this treatment can improve physical behaviour, brain cell injury and inflammation. If successful, we believe we may have enough evidence to apply for further funding to next test ACE-Is in ICH patients. As we already know that ACE-Is are safe for patients, this exciting study holds real potential to accelerate this treatment into the clinic within the next 10 years. 

Sarah Herrick

Novel hydrogel-based drug delivery strategies to prevent surgical adhesions

In this project we will pioneer new experimental treatments for adhesions. These are Internal scars that are side effects after various types of surgery to the gut and other internal organs. Adhesions can cause severe pain and even life-threatening gut blockage. Adhesions can also prevent women from having successful pregnancies. Unfortunately, there are currently no effective ways to prevent or cure adhesions and so they continue to seriously impact on many people in the UK, with great misery and financial cost. In our laboratory study we are pioneering a new type of treatment that uses special proteins called “growth factors” that are released from small drops of “gels” that are placed near the site of surgery. We believe that this strategy will markedly reduce the tendency to scar. If our study is successful, the next steps would be to test the treatment in people and hopefully reduce much long-term suffering.

Steven Rogers

Developing Artificial Intelligence based computational modelling software for the prediction of cardiovascular events in high-risk patients

Previous research tells us that screening people with narrowing’s or blockages of the arteries (called cardiovascular disease) helps them take their medication better which in turn can reduce the number of heart attacks or strokes. In the general population, the number of people with cardiovascular disease is high, but the number of heart attacks or strokes remain low (<2%). Patients with diseases like Abdominal Aortic Aneurysm (AAA), for example, are considered high-risk because they are more likely to have cardiovascular disease, such as a narrowing in an artery in the neck (called carotid artery disease) which supplies the brain with blood and as a result, larger numbers have the heart attacks or strokes (9-17%).

Compared with general populations, selectively screening high-risk groups (like those with AAA) may be beneficial, especially considering carotid artery disease is highly predictive of those who will have either a heart attack or a stroke. We also know that this selective screening focused on high-risk populations, rather than the general population, is better value for money. Clearly, if screening was undertaken to identify those people with carotid artery disease, we might be able to reduce the number of people who have heart attacks and strokes with better medication and education.

One way to identify which AAA patients have carotid artery disease is by using CT or MRI scans. However, these are expensive, involve X-rays or use a dye that can harm the kidneys, making them less than ideal. Ultrasound is cheaper but requires skilled staff, of which there is a shortage. For successful ultrasound-based screening, there must be technological developments to solve this.

Tomographic 3D ultrasound (tUS) is a simple scanning method taught in 20-minutes. Artificial Intelligence (AI) can be trained to calculate measurements of cardiovascular disease. AI is where jobs usually done by a human can be done automatically by a computer. This work currently calculates how much carotid artery disease is forming a narrowing. Although this is useful, it ignores how the blood flow is affected by this narrowing. Computational Fluid Dynamics (CFD) is an engineering technique that can assess how the blood flow is affected by things like narrowing’s. It can be used to identify which patients with carotid disease might go on to have a heart attack or stroke. Although helpful, current CFD tools require an experienced engineer and require a lot of resources. This would not be ideal for screening as there are not enough engineers or resources to allow its daily use in the NHS.

This current study will use tUS because it is cheap, AI as it can automate process to get round the lack of staff and CFD as it might be a better way to identify those people at risk of heart attack or stroke. If successful it would enable the introduction of personalized screening that is good value-for-money for the NHS.

Shruti Garg

Optimizing non-invasive brain stimulation for working memory difficulties in Neurofibromatosis

Neurofibromatosis 1 (NF1) is a common genetic condition which affect 1 in 2700 people. Much of the real-life impact of NF1 on children relates to learning and behavioural difficulties with long-term consequences on academic and occupational functioning. Problems with ‘working memory’ (WM), which are particularly relevant for day-to-day functioning for listening to and remembering short-term information, following instructions, reasoning and making decisions affect up to 70% of all children with NF1. Currently, there are no effective treatments for these impairments. Our research group has tested novel non-invasive brain stimulation (NIBS) treatments for working memory problems in NF1. We have demonstrated that using this treatment is safe, feasible, acceptable to families and has the potential to improve working memory problems. Using advanced MRI brain imaging techniques, we have recently shown the effects of NIBS on the brain push/pull neurotransmitters (GABA/Glutamate), known to be affected in NF1.  In this new study, we will refine the NIBS intervention through further experimental testing to understand how individual patient differences affect their response to treatment. We will use advanced MRI imaging and computational modelling to investigate how the current type (direct/alternating), frequency, intensity and duration affect brain plasticity, and ultimately the effect of the intervention. Further, we will investigate how individual patient differences in skull thickness and brain structure contribute to the differences in the response to NIBS. The advantage of NIBS is its low cost cand potential for it to be applicable across different clinical conditions. The treatment developed in the context of NF1 may be applicable to other rare disorders associated with learning problems.

Tom Jowitt

Tools for stem cell biomarker identification

Stem cells are the precursor to specialized cells with individual functions. In the body, stem cells divide to become specialized cells in response to certain chemical stimuli, such as chondrocytes in the knees or podocytes in the kidneys. This process is called differentiation. Differentiation of stem cells into different cell lineages can be performed in the laboratory and has therapeutic potential. There are an increasing amount of stem cell therapies reaching clinic and the stem cell therapy market is growing rapidly. When growing stem cells, there is a need to constantly ensure cell-culture expansion without deterioration or differentiation and it is particularly important to pick up changes in the stem cells very early before these become irreversible and the cells are lost to differentiation. This project aims to simplify the process of identification of stem cell health. One way to do this is to monitor the levels of biomarker proteins that the cells produce into their culture environment. We have previously identified ratios of protein biomarkers which can define stem cell health and these protein biomarker ratios change significantly within 24-36h of initiation of a detrimental culture environment. Thus they can be measured from samples of growth medium without having to waste the cells. To monitor these biomarker proteins we need specialist assays and tools with which to identify their levels in complex cell-growth media. To do this we will develop antibody-like molecules called nanobodies which can specifically interact with the biomarkers and provide a readout of biomarker concentration in the cell culture media.  This award is to develop these nanobody tools prior to development of a biosensor platform to monitor these biomarkers in real-time. This will be vital in the pathway towards commercial sensor development to monitor stem cell health.

Stephen Taylor

Re-purposing cabazitaxel to overcome drug pump-mediated taxane resistance in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) is the most prevalent and deadly ovarian cancer subtype. With limited treatment options, taxanes such as paclitaxel play a major role in treating both newly diagnosed and relapsed HGSOC. However, while many patients initially respond well to treatment, most eventually develop drug-resistant disease. One way by which cancer cells can become resistant to taxanes is by increasing production of transporter proteins, such as ABCB1 (aka Mdr1 or p-glycoprotein), which efficiently pump drug out of cancer cells before any damage is caused. Since HGSOC cells display extensive genome instability, they can inadvertently create chromosome re-arrangements, or translocations, that result in increased production of ABCB1. Such translocations have been detected in 18.5% of recurrent HGSOC, and are associated with paclitaxel resistance.

Although drugs have been developed to block drug transporters, clinical studies evaluating their ability to enhance chemotherapy were unsuccessful, due to unacceptable toxicity and/or limited improvement. However, since these studies did not apply selection to only include cancers with drug resistance due to excess transporters, many of the patients included were unlikely to benefit. Nonetheless, the research community has since been reluctant to further investigate strategies to overcome drug pump-related drug resistance.

Meanwhile, the novel taxane cabazitaxel has been created with chemical modifications designed to evade drug transporters and is already available to treat drug-resistant prostate cancer. We aim to demonstrate the potential of cabazitaxel to treat HGSOC that has specifically developed translocations of ABCB1. The project is facilitated by our unique living biobank of >120 patient-derived ovarian cancer models (OCMs), which retain the molecular characteristics of the original tumour, are clinically annotated, and amenable to high-resolution drug-sensitivity profiling and genomic analysis [1]. We have already identified five OCMs with ABCB1 translocations using nanopore-based DNA sequencing. Importantly, we have analysed one of these five, finding that, while resistant to paclitaxel, it is sensitive to cabazitaxel. We now aim to confirm that ABCB1 translocations are associated with paclitaxel-resistance and cabazitaxel-sensitivity in a larger cohort of 10­–20 OCMs to be identified by nanopore sequencing. In addition, we aim to demonstrate the ability of nanopore sequencing to detect ABCB1 translocations using fresh HGSOC ascites samples. Ascites form in patients with HGSOC as cancer cells and fluid collect in the peritoneal cavity, and the requirement to frequently drain this fluid provides a safe and repeat method for sampling HGSOC tumour cells for testing. Our research will therefore generate the evidence-base and enthusiasm required to progress cabazitaxel along the translational pathway, and help inform patient selection for potential future clinical studies.

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