Health Innovation Challenge Fund: projects we've funded
Next generation engineered T-cell therapy for brain lymphoma
Most patients with aggressive brain lymphoma die of their disease. T-cells are white blood cells that are part of our immune system. T-cells can be imagined as ‘robots’ moving through the body on a ‘seek-and-destroy’ mission against virus-infected cells. T-cells do not normally attack lymphoma cells, only infected cells. However, it is possible to genetically engineer T-cells taken from a patient's blood so they recognise lymphoma cells. These engineered T-cells are called ’CAR T-cells‘ and once they are reinjected into the patient, they find and kill lymphoma cells.
Dr Martin Pule at University College London will test a CAR T-cell treatment for aggressive brain lymphoma in a clinical study. While CAR T-cells may be good treatments for lymphoma outside the brain, treating brain lymphoma is harder: the brain is more difficult to reach than other parts of the body. Additionally, when CAR T-cells work quickly, they cause inflammation which the brain may not tolerate compared with other organs. The project plans to engineer CAR T-cells in an advanced way so that the team can track them using a special MRI scanner and control how quickly they work with a drug. This will help to safely and effectively develop the new treatment.
GOLD imaging in acute stroke: further technology development incorporating a perfluorocarbon oxygen carrier (Oxycyte)
Acute ischaemic stroke is common and disabling, but lacks acute treatment options. The thrombolytic drug rt-PA (alteplase), given within 4.5 hours of onset based on clinical symptoms and basic brain imaging, significantly increases independent recovery, but is under-utilised (<5% of UK patients). Advanced brain imaging offers a means of targeting treatment to a wider population but existing technologies are not widely used because of additional time incurred, and limited diagnostic validation.
GOLD (Glasgow-Oxygen-Level-Dependent) is a new combined diagnostic and therapeutic approach in which an IV oxygen carrier perfluorocrabon (Oxycyte) enhances imaging of brain metabolic responses to inhaled oxygen with MRI, differentiating potentially salvageable penumbral tissue from irreversibly damaged tissue. Unlike alternatives, additional imaging time carries no penalty (“time lost is brain lost”) since PFC+oxygen maintains brain viability and reduces ischaemic damage.
The project's goals are to optimise dose for diagnostic sensitivity and to confirm Oxycyte+50%O2 preclinical safety when coadministered with thrombolytics and radiological contrast agents. The project also aims to establish safety and tolerability in acute ischaemic stroke patients in an ascending dose, randomised, controlled study and confirm diagnostic imaging feasibility in stroke patients. GOLD, developed by Professor Keith Muir and Dr Celestine Santosh, will allow individual treatment decisions based on brain pathophysiology, not time alone, widening eligibility and improving safety of rtPA, and stratifying patients for future research.
Clinical validation of eye movement abnormalities as diagnostic biomarkers of psychiatric disorders
Unlike other branches of medicine there are currently no tests to help with the diagnosis of psychiatric disorders such as schizophrenia, bipolar disorder and recurrent depression. Diagnosis is based solely on patient history, symptoms and observed behaviour. This means that diagnoses are unreliable and patients often get the wrong diagnosis and treatment.
Dr Philip Benson and Professor David St Clair from the University of Aberdeen have discovered that a battery of tests based on simple eye movement recordings when watching pictures is a good diagnostic method for a range of major psychiatric disorders. This technology is better than any blood, radiology or gene based tests.
Saccade Diagnostics, in collaboration with Dr Benson and Professor St Clair and also Professor Andrew Mcintosh from the University of Edinburgh, have received a Health Innovation Challenge Fund award to replicate the team’s exciting findings on new sets of patients with schizophrenia, bipolar disorder and recurrent depression. They will also test a large group of community based people with depression and normal subjects and also patients attending hospital with borderline personality and obsessive compulsive disorders.
If the new findings are as good as the existing ones, the technology will be developed for use in diagnosis, risk evaluation and management of individuals with major psychiatric disorders. It will improve patient wellbeing, satisfy an enormous unmet need and reduce costs in the NHS and other healthcare services worldwide.
Automatic anomaly detection for brain imaging triage and classification
Modern brain imaging contains vastly more information than historical radiographs, yet its clinically informative output has remained the same: a radiologist’s verbal report. As the information content of imaging increases, a void has opened between what we expensively collect and what we actually use.
This is both a lost opportunity, and an obstacle to the continued growth of brain imaging. Technology being developed by Dr Parashkev Nachev and colleagues at University College London seeks to close this gap by applying novel computer-assisted algorithms so as to exploit much more of the information in each scan than a verbal report contains. An automatic “anomaly map” for each scan, indexing the deviation from normality of each point, will assist radiological reporting, allow the application of computer systems that predict clinical outcomes from patterns of anomaly, and guide radiological triage and resource/performance management.
The project aims to demonstrate the feasibility, robustness, clinical, and managerial value of the approach using a large collection of standard brain imaging, and to deliver a pilot system capable of translation into a full clinical product. Without changing any clinical pathways or adding new investigations, the system will improve radiological reporting and optimise radiological triage and management, while creating a scalable major new platform for computational imaging analysis.
An automated tool to identify vertebral fractures in various imaging modalities
Osteoporosis is a condition in which patients have too little bone, and so are more prone to suffering fractures, most commonly in the spine, wrist and hip. These lead to pain and deformity and often death. Osteoporosis affects 1 in 2 women and 1 in 5 men over age 50 years. The treatment of fractures will cost £2 billion in UK by 2020.
Vertebral fractures are the most common fractures in osteoporosis, and if present indicate that the patient is at significantly increased risk of future fractures and should be treated. However, over 50% of vertebral fractures are not associated with symptoms and so their presence may not be suspected, and are often not reported if present on various imaging techniques. Professor Tim Cootes and colleagues at University of Manchester have developed world-leading technology for locating and analysing bones in medical images.
In collaboration with Optasia-Medical Ltd and Central Manchester University Hospitals they will develop a fully automated computer tool for identifying vertebral fractures on X-ray images. This will be designed to be easy to use and will be suitable for adoption within the NHS. They will demonstrate the tool’s performance by installing a system in an NHS radiology department and testing it on routinely collected clinical images. By identifying subjects with vertebral fractures who would benefit from referral for further assessment for osteoporosis the system should ultimately reduce the number of fractures, including the numbers of potentially fatal hip fractures.
Virtual coronary physiology: an angiogram is all you need
Disease inside the heart’s arteries kills more people in the UK than anything else. Dr Julian Gunn and his team at the University of Sheffield have developed a computer system called 'VIRTU', which predicts blood pressure changes inside coronary arteries.
This is important because doctors make better decisions regarding when and how to treat patients with coronary artery disease if they have these blood pressure measurements. Currently, doctors have to insert a metal wire inside the heart to measure artery pressures. This is time-consuming and requires special equipment, staff and medicines. Although this invasive technique saves lives and money, more than 95% of patients do not receive the procedure and thus do not get the benefits that it can provide.
VIRTU provides a solution to this problem since it only needs X-ray pictures and does not require any wires, drugs, or additional time, equipment or staff. This project aims to improve the speed and accuracy of VIRTU and test it in people with more complicated coronary disease so that eventually it can be used in all patients. The research will make VIRTU 'patient-ready' and will deliver all the advantages of the current invasive technique (i.e. reduced deaths, heart attacks and cost) whilst being less invasive and usable in 100% of patients.
Comprehensive molecular diagnostics for inherited cardiac conditions
Some diseases of the heart run in families (inherited cardiac conditions). In the UK they are the most common cause of sudden death in the young and a major cause of death and disability across all age groups. Although we know a lot about the genes that cause these diseases and healthcare experts around the world advise that genetic test should be used routinely to guide healthcare decisions, they are in fact rarely and inequitably used for inherited cardiac conditions.
A research group headed by Professor Stuart Cook at Imperial College London, working with Colleagues at the Royal Brompton and Harefield NHS Trust, will use cutting edge sequencing technology to test all the known genes that cause these diseases in a single test. The test will provide faster, more affordable and far more comprehensive and accurate genetic testing than currently available and will change the way we treat patients and their families.
Rapid detection and treatment of ventilator-associated pneumonia - towards improved antibiotic stewardship
Critically ill patients whose lungs are supported by breathing machines (ventilators) commonly develop new lung infection, called ventilator-associated pneumonia (VAP). Because VAP is often fatal, antibiotics are administered whenever it is suspected.
However VAP is hard to distinguish from several non-infective lung conditions and most patients with suspected VAP do not have pneumonia. Therefore many patients receive unnecessary antibiotics for several days, promoting emergence of 'superbugs'. Laboratory infection results for VAP typically return in 3 days. A simple test rapidly and confidently excluding VAP would improve patient care, reduce unnecessary antibiotics and decrease costs.
Professor John Simpson and his team at University of Newcastle has recently showed that low levels of specific proteins in fluid from the lungs of patients with suspected VAP effectively excluded VAP within 4 hours. The test used is an extension of existing technology produced by the team's commercial partner Becton Dickinson (BD) Biosciences. This test will be rigorously analysed in a clinical trial and if rapid, safe, cost-effective reductions in unnecessary antibiotics are confirmed the test will be rapidly introduced into hospitals through the commercialisation expertise of the University of Newcastle technology transfer team and BD Biosciences. Every intensive care unit worldwide deals with suspected VAP, and this new test would have a significant global healthcare impact.
Immediate point of care molecular diagnostics for lung inflammation/infection in critical care
At least 40% of all patients in ICU need a ventilator to support their lungs, with many associated complications. Once established on mechanical ventilation, critically ill patients are at risk of Acute Lung Injury (ALI) and secondary infection resulting in ventilator associated pneumonia (VAP). Both ALI and VAP increase hospital mortality, illness costs and result in poor functional long-term patient outcomes.
Professor Chris Haslett's team at Edinburgh University aims to develop a technology to improve the diagnosis of these lung diseases. The team will synthesise and test in vitro and in vivo three novel smart probes. These novel imaging agents in conjunction with revolutionary techniques will be designed to detect the presence of neutrophilic infiltration, the presence of bacteria at sites of lung injury, the gram-status of the bacteria, and the presence of MRSA.
This technology has the potential to determine at the earliest possible stage which patients in ICU are developing secondary infection, identifying the organism responsible and allow rapid and accurate detection/exclusion of hospital-acquired infections. It could also provide a rapid, 'real-time' in situ approach to establishing mechanism-based efficacy of new drugs.
Development and application of a targeted array test to diagnose and direct therapy in haematological cancers
Leukaemia is a form of cancer that affects blood cells and arises in the bone marrow or lymphoid organs. There are several types of leukaemia, depending on which blood cells are affected.
Although several treatments are available, the current genetic tests used to guide therapy are not sufficiently precise. This means that some patients suffering from leukaemia may not respond to treatment or may suffer adverse side-effects. In order to be most effective, treatment must be tailored to the individual. This is also important when considering emerging therapies that are extremely expensive and must be used judiciously.
Dr Sam Knight and colleagues at University of Oxford have developed specialized approaches that use microarray technology to test, in detail, the genetic make-up of blood cells from patients with B-cell chronic lymphocytic leukaemia. During their three year HIC Fund study, these approaches will be validated and adapted specifically for use in a clinical setting. The more precise detection of relevant genetic alterations will enable doctors to provide the most suitable treatment for patients, minimizing side-effects of treatment, reducing mortality and NHS care costs. The approach will be suitable for use in hospital laboratories worldwide.
Hospital Alerting via Electronic Noticeboard (HAVEN)
Hospitalised patients may suffer deterioration in their medical condition, or develop a complication of their illness such as a chest infection or life-threatening blood clot. Hospital staff monitor patients for these problems using “vital signs” such as temperature and blood pressure. However, in spite of advances in the way the vital signs are recorded and assessed, in the UK each year 40,000 inpatients deteriorate sufficiently to require admission to an intensive care unit, 10,000 of which subsequently die.
Modern hospitals now collect much information electronically, including patient descriptors (for example age and previous admissions), laboratory results, and vital signs. When clinicians assess patients they mentally weigh up each of these pieces of information to gauge how ill the patient is at the time, and their likely future course. Clinicians and clinical managers can only do this one patient at a time.
A research group at the University of Oxford headed by Dr Peter Watkinson plans to produce a hospital-wide IT system that makes this risk assessment in all hospital patients continuously. The score will be made available via a display specifically designed to allow expert clinicians to identify and rank at-risk patients quickly and initiate treatment. The aim is to deliver a validated prototype system ready for commercialisation in partnership with industry.
Improving patient assessment after stroke: The Cambridge and Oxford Automated Screening Test (COAST)
Every year 150,000 UK residents suffer a stroke. Cognitive problems (e.g. difficulties with language) and low mood are common and undermine recovery. Consequently NHS guidelines recommend that all patients have brief test ‘screens’ to detect these problems and better target care. Unfortunately, due to a lack of materials, skilled staff and staff-time, audits show these targets are often unmet.
The Cambridge and Oxford Automated Screening Test (COAST) is designed to solve this problem. It is a set of brief computerised cognitive and mood measures, easily administered by staff using touchscreen tablets. COAST guides health workers through the tests, collects responses from patients, and automatically generates clinical reports.
The tests are specially designed to detect problems prevalent after stroke and to include all patients. It is highly portable and requires no specialist equipment beyond devices already widely in use. It frees staff from administrative chores allowing increased patient contact.
A project team led by Dr Tom Manly (MRC Cambridge) and Professor Glyn Humphreys (University of Oxford) have developed COAST from a rigorous evidence-base. The award will support the crucial final stages of the project (collecting assessment results from patient and healthy populations and NHS field trials), enabling COAST to make a real difference to clinical care within 3 years.
Accurate and patient-friendly measurement of binocular visual function using a 3D smartphone
Stereo vision, often called 3D vision, is the ability to use both eyes together to see depth. Clinicians use specialised vision tests, called stereotests, to measure patients’ 3D vision in disorders like squint. This helps them monitor progress, assess whether treatment is helping, and can guide decisions like when to operate. However, existing stereotests are not very reliable. Young children may not understand the test or be willing to cooperate, e.g. by wearing 3D glasses. This limits the usefulness of current stereotests.
Recently, the first glasses-free 3D tablet computers have come on the market. A team led by Dr Jenny Read at Newcastle University wants to use these to produce a better stereotest. For children, the stereotest will be embedded in a fun, colourful game. Patients will give their answers by touching the screen. The device will use these responses to interactively adapt the test for that particular patient, customising it for each individual. The device will monitor patients while they do the test and automatically correct for any changes in viewing distance.
As a result, it will provide clinicians with more accurate data on 3D vision, especially in small children. This will help healthcare professionals to track the progress of treatment and make the best clinical decisions.
Real-time Adaptive & Predictive Indicator of Deterioration (RAPID)
Of the 1.5 million children admitted to UK hospitals every year; 650 suffer cardiac arrests and 3000 die. Most have signs that indicate deterioration before the life-threatening event. Current early warning scores have reduced avoidable life-threatening illness and death, but these systems need to be improved.
Deterioration can be missed when vital signs change rapidly, observations are made infrequently and slowly deteriorating trends can occur between alarm thresholds. A team led by Dr Heather Duncan of Birmingham Children's Hospital NHS Foundation Trust proposes a system where continuous observations are taken from patients and this data is used to understand, in real-time, what is normal for each patient and detect the changing patterns in their physiology.
Small chest and hand sensors wirelessly connect patients in the wards. Continuous monitoring allows deterioration to be recognised, triggering an alert and provoking timely intervention to prevent patients suffering further deterioration and death.
The technology uses software adapted from Formula 1, with Aston University and Birmingham Children’s Hospital algorithms to interface seamlessly with NHS IT systems. The key goals are to deploy RAPID in two cardiac wards, demonstrate reliable collection and processing of data, provide clinical interpretation of processed data and create new patient pathways for better and more effective utilisation of nursing and doctors.
Post-Intensive care risk-adjusted alerting and monitoring
One tenth of the 85,000 patients discharged annually from UK intensive care units (ICUs) apparently recovering from their acute illness, die before leaving hospital. Frequent visits to the patients' wards by the ICU nursing team reduce this risk but suitably trained nurses are expensive and in short supply.
A research team in Oxford led by Dr J. Duncan Young plans to develop a comfortable wearable physiological monitoring device linked to computers with 'knowledge' of patterns of vital signs in post-ICU patients to automatically measure vital signs, and detect warning signs of serious problems, in patients discharged from the ICU.
Using the hospital wi-fi network they will monitor the patients' vital signs continuously with a computer system, which will be programmed with information on each individual patient's risk of deterioration obtained during their ICU stay. If the computer detects a change in the patients' vital signs, it will alert medical staff.
This approach will allow hospitals to monitor far more patients for a far longer time than would be possible using nurses alone, whilst minimising false alarms by tailoring the alarm limits to each individual patient. Even modestly reducing these post-ICU deaths to one in twelve discharged patients would save 1,400 lives annually, equivalent to more than half the road deaths in Great Britain. Compliance with government guidance, reduced costs, improved safety and a reduction in insurance premiums will all be used to persuade healthcare teams to adopt the system.
Open-architecture telehealth platform for COPD
COPD affects 210 million people globally, with 50% of costs (unplanned hospital admissions) that could be avoided with more responsive models of care. 30% of COPD patients in the NHS are re-admitted to hospital once within the year. Within 10 years, COPD will become the third leading cause of death. Even if everyone stopped smoking today, the effect on COPD statistics would not be seen for up to 20 years.
A research group headed by Professor Lionel Tarassenko at University of Oxford proposes to develop an easy-to-use system for patients to monitor their condition, based on mobile communications technology (hence the name of mHealth). The project will make use of the latest generation of smartphones and tablets to enable COPD sufferers to complete patient diaries, respond early to worsening symptoms, and receive support from a respiratory nurse who has access to all of their data.
This will lead to improved self-management and a higher quality of life for these patients, with a reduction in the number of severe exacerbations which they experience and which require an unplanned and costly hospital admission. A key goal of their approach is to bring the costs of telehealth technology by at least an order of magnitude to enable it to be adopted on a much larger scale than at present.
Monitoring of upper limb rehabilitation and recovery after stroke through gaming
Stroke frequently damages the area of the brain controlling movement, as a consequence there are thousands of people with weakness down one side of their body. This has a major impact on their lives because everyday activities require two hands.
The brain can relearn control of the weak arm, but this needs frequent therapy over many months. There are not enough therapists to provide this on a one-to-one basis and fewer than 20% of patients regain independence after a stroke. Professor Janet Eyre and her team at University of Newcastle have developed a library of video-games to be played at home, which provide highly motivating therapy for relearning arm and hand movements.
The aim of the project is to analyse information about patients' performance of arm and hand movements during the video games in order to provide feedback to the patient and their therapist via the internet. This will enable effective rehabilitation of arm and hand movements to be delivered at home at times and places to suit patients, whilst still maintaining expert supervision from a therapist. The need for hospital visits will be greatly reduced, patients will have the opportunity to undertake more frequent therapy sessions, therapists will be able to supervise more patients and patients should regain greater independence.
Re-purposing of 13-cis-retinoic acid for children with neuroblastoma
Neuroblastoma is a rare and aggressive cancer that predominantly affects children aged 5 years or less. Children with neuroblastoma are commonly treated with a combination of therapies including a drug called 13-cis-retinoic acid (13-CRA). Treatment with 13-CRA improves survival chances of children with neuroblastoma and is standard therapy for this disease worldwide.
Presently, 13-CRA is only available as a capsule. As few young children will take capsules, carers often have to administer the drug by first extracting liquid out of the capsule. Studies show that this method of administration commonly results in children being given the wrong dose of drug which, in turn, increases risks of treatment failure and drug toxicity. Furthermore, since 13-CRA can cause birth defects, pregnant women (e.g. parent of a child with NBL) risk accidently exposing their unborn babies when drawing up the drug from capsules.
Despite requests by governmental agencies, no manufacturer has yet developed a child-friendly preparation of 13-CRA. Dr Hussain Mulla, Head of Clinical Development at Nova Laboratories Limited and his team aim to develop a fully tested oral liquid preparation of 13-CRA as an unlicensed special medication for the NHS for use in children with neuroblastoma. This product will be available in the United Kingdom and Ireland and may be available elsewhere subject to the local regulatory environment and addresses an unmet need for children with a disease that still has poor outcomes.
Protecting organ function in severe trauma/haemorrhage using the anti-malarial drug artesunate
Trauma is the most frequent cause of death in people under the age of 40. Despite resuscitation in the emergency room, severe blood loss can lead to the dysfunction of vital organs (kidney, lung, heart, liver, brain), which ultimately may cause the death of a trauma patient. At present there are no specific treatments for organ failure in routine clinical use, and management is only supportive.
A research group headed by Professor Christoph Thiemermann at Queen Mary University of London, has discovered that small doses of a commonly used and safe anti-malarial drug (artesunate), reduces multiple organ failure after trauma-haemorrhage in a rat model. The team at Queen Mary's plan to conduct a trial with artesunate in patients with trauma and severe haemorrhage.
The team hopes to demonstrate that this therapeutic agent is safe and also effective at reducing the incidence and severity of multiple organ failure. This early treatment of trauma patients against organ failure could have a major positive global impact on patient outcomes and resource utilisation.
Repurposing anti-TNF for treating Dupuytren’s disease
Dupuytren’s disease is a very common condition, affecting 4% of the general UK population. It causes the fingers to curl into the palm and can be extremely disabling. There is no approved treatment for early disease. Once patients have established deformities, the diseased tissue is removed surgically or cut using less invasive techniques such as a needle or an enzyme.
However, recovery following surgery usually takes several months and recurrence rates with the non-surgical techniques are high. A team from the University of Oxford led by Professor Nanchahal has unravelled the molecular mechanisms that initiate and maintain the disease process. Based on these findings they plan to test a new treatment with anti-TNF, a drug currently approved for use in patients with rheumatoid arthritis. If effective, this will represent the first targeted therapy involving a simple injection for patients with early Dupuytren’s disease that will preserve hand function and avoid the need for subsequent more invasive treatments such as surgery.
Albumin to prevent infection in Acute-on-Chronic Liver Failure (ATTIRE)
Liver disease is the 5th commonest cause of death in the UK and the only one of the top 10 currently rising. Approximately 110,000 patients with symptoms of advanced cirrhosis, (commonly related to alcohol excess) e.g. jaundice, confusion and bleeding from the stomach, were admitted to UK hospitals in 2011-12.
The most common cause of death in these patients is infection. These patients have a weakened immune system making them highly vulnerable to infection and no effective strategy exists to improve this. A research group headed by Dr Alastair O’Brien at University College London discovered that the cause of this vulnerability is an increase in blood levels of a lipid hormone called Prostaglandin E2 (PGE2) which reduces white blood cell function, the cells that fight infection.
Dr O’Brien and colleagues have discovered that patients’ immune systems can be boosted for at least 24 hours by infusing albumin into a vein which reduces PGE2’s effects. This safe process is currently given when patients need extra fluid e.g. those with kidney damage. The group propose this new exciting use for albumin to be given daily to improve cirrhosis patients’ immune systems and therefore prevent infection. The long-term goal is that this will save lives and reduce health-care costs and propose to investigate this in a large scale clinical trial.
Topical tropomyosin kinase inhibitor as a treatment for inherited CYLD defective skin tumours
Approximately 1 in 100,000 people in the UK suffer from a rare genetic condition that leads to the development of multiple, disfiguring, skin tumours called cylindromas on the scalp. The condition is caused by an inherited mutation in the CYLD tumour suppressor gene.
Up to 1 in 4 affected patients require complete scalp excision to control tumour burden. These patients also develop tumours on the body that require surgery when they become painful or impair function due to their size.
Researchers at Newcastle University and the Institute of Cancer Research, London, conducted whole genome molecular profiling experiments that led to the discovery of an attractive molecular target in these skin tumour cells, named Tropomyosin kinase (TRK). Now, a team led by Dr Neil Rajan at Newcastle University will conduct a trial of the topical TRK inhibitor CT327, developed by a European biotechnology company known as Creabilis, in patients with CYLD genetic mutations.
The team hopes to demonstrate that delivering a TRK inhibitor to patients with this inherited skin tumour may represent a safe and feasible treatment for early tumours and reduce the need for surgical interventions.
The HAEM (Haemorrhage and Antifibrinolytics in Emergency Medicine) Project
Sudden severe bleeding is an important medical problem in the UK and worldwide. Recent results from a large international clinical trial in bleeding accident victims show that a cheap drug called tranexamic acid reduces the chances of dying from the injuries and improves other patient outcomes without any increase in side effects.
Tranexamic acid is not a new drug. It has been used to control bleeding during major surgical operations for many years. The realisation that this drug could be used to treat a much wider range of bleeding conditions holds the promise of important benefits for patients at low cost.
The research team, lead by Professor Ian Roberts at the London School of Hygiene and Tropical Medicine, responsible for the accident victim research are now conducting a trial to see if this drug improves outcome in post-partum bleeding.
Genetics and genomics
Pre-clinical development of a stem cell based gene therapy protocol and clinical proof of principle for Duchenne muscular dystrophy
Stem cells have the potential to cure many severe and currently untreatable diseases. Among these is Duchenne muscular dystrophy (DMD) which is a relatively frequent (1:4,000 males), X-linked, genetic disease, characterised by lack of the protein dystrophin which leads to progressive deterioration of skeletal and cardiac muscle, leading to a variable but progressive limitation of the patient’s mobility and heart and/or respiratory failure.
Professor Guilio Cossu and his team from the University of Manchester will examine the effect of correcting the genetic defect in the cells of patients and injecting them back into the foot muscle. Initially the project will examine the safety of this procedure before examining its efficacy. The cells will be also be injected into the muscle of the thumb of the dominant hand, aiming to increase its force of contraction, hand mobility and the patient’s quality of life.
First-in-human trial of an optimised lentiviral vector for cystic fibrosis ne therapy
Cystic Fibrosis (CF) is a genetic condition that shortens patients' lives, usually because of lung disease. A person with CF inherits two faulty copies of a gene called CFTR, one from each parent. Lacking normal CFTR, CF lungs become clogged with sticky mucus and cannot easily get rid of inhaled bacteria and viruses that damage the lungs. The annual cost of treating the 10,000 UK patients is ~£300million. Time-consuming treatments such as antibiotics and physiotherapy slow down, but don’t stop, the lung disease. New drugs can improve lung function in some patients, but effective medicines to treat lung disease in all CF patients are required.
A team led by Chris Boyd (Edinburgh), Eric Alton (Imperial College) and Stephen Hyde (Oxford) have made a new gene therapy product designed to meet this need by putting normal CFTR genes into patients' lungs. The new gene therapy was developed from a virus to make it better at getting into nose and lung cells, and the team want to make it suitable for a clinical trial. The ultimate aim is to bring the gene therapy into clinical use to treat CF lung disease.
The Application of Next Generation Sequencing (NGS) to the analysis of Minimal Residual Disease (MRD) in Childhood Acute Lymphoblastic Leukaemia (ALL)
Each year in the UK there are approximately 400 new cases of childhood ALL and 30 cases of relapsed ALL. It is really important if this treatment is to be successful to use a marker, known as Minimal Residual Disease (MRD) that indicates risk so that the treatment can be tailored to each child.
Although extremely helpful, the current method of measuring MRD is time consuming, expensive, complicated and doesn’t give a result for all children.
A team led by Dr John Moppett of University Hospitals Bristol NHS Foundation Trust is developing a new method that will enable delivery of a cheaper, faster and more sensitive test, involving more patients, whilst also enabling further understanding of why children with the disease sometimes relapse.
Applications of next generation sequencing in newborn screening
UK newborn babies are currently screened for five rare disorders using dried blood spots (DBS) taken shortly after birth and four further disorders will be added in 2015. Screening use biochemical tests performed on the DBS to identify babies affected with these conditions. Some “screen-positive” babies have genetic tests to confirm the disorder. The disorders being tested are potentially life-threatening but are treatable if identified early.
The severity of the disorders differs between patients. The link between genetic defects (mutations) and the disorder severity are not well understood. To improve knowledge of the link between mutations and symptoms/severity, a team jointly lead by Dr Ann Dalton (Sheffield Children’s NHS Foundation Trust) and Prof Anne Goodeve (University of Sheffield) proposes to use a new technology, next generation sequencing (NGS), to find mutations in six screened disorders.
The researchers will collect details of patients’ symptoms, blood chemicals and mutations in a database to understand the links between them for each disorder. This will help provide more appropriate and personalised treatment to affected babies. They will also investigate whether NGS could be used to identify patients with disorders having no abnormal chemicals in the blood by creating a system to deliver rapid genetic results which could be used for NBS and other purposes.
Prenatal Assessment of Genomes and Exomes (PAGE)
Women have ultrasound scans of their baby in pregnancy to check for structural abnormalities (such as a heart defect). If a problem is found, women are offered prenatal testing to check for chromosomal abnormalities in the baby, such as Down’s syndrome. This helps to predict the outcome for the child.
The chromosomes in our cells consist of strands of DNA which encode all the genes. Standard genetic testing detects large chromosomal changes that can be seen down a microscope. In some centres additional testing can detect smaller chromosomal changes. Dr Matthew Hurles at the Wellcome Trust Sanger Institute and colleagues plan to look in the greatest possible detail, down to the level of individual building blocks of DNA, to examine the genes.
In this study, as the amount of information generated by this testing is vast and the interpretation time-consuming, results cannot be given during the pregnancy. If a genetic reason for the abnormal scan findings is found, this information would be given to parents after pregnancy. This could provide important information about the health of the child or implications for future pregnancies. This research will allow the team to discover new genes responsible for causing abnormalities and, if appropriate, to develop methods for speedy feedback of important information during pregnancy in the future.
Translation of whole genome sequencing into clinical practice
Genetic diseases occur when changes in a particular gene (called mutations) disrupt its normal function. There are many diseases that are caused by mutations in an individual’s DNA sequence.
However, our knowledge of the causative genes is often incomplete, and many patients remain undiagnosed even when all possible tests have been performed. Furthermore the testing process is slow since genes are often tested one at a time, for technical and economic reasons.
A research group headed by Dr Jenny Taylor at University of Oxford is aiming to improve this situation, by working out how new DNA sequencing technology, which can test an individual’s whole DNA sequence at once, can be used for genetic testing in the NHS. This should lead to much higher rates of success in diagnosing genetic conditions.
However, there are many technological hurdles to overcome in the collection and use of this ‘whole genome’ sequence data, and the way in which genetic testing is conducted in the NHS will need to adapt. Their goal will be to ensure that this new sequencing technology is rolled out in the NHS in a socially responsible manner so that any patient with a genetic disease can benefit, providing a benchmark for the NHS more widely, and other countries.
Fully integrated, real-time detection, diagnosis and control of community diarrhoeal disease clusters and outbreaks
Seventeen million people suffer a diarrhoeal disease every year. These diseases often lead to outbreaks of infections, like norovirus - now among the costliest infectious burdens on the NHS.
The sooner diseases are detected, the sooner they can be brought under control - limiting their health and financial impact. It is known from outbreaks of Escherichia coli O104 in Germany and O157 at Godstone Farm in Surrey that surveillance is key to detection, but with fewer people now consulting their GP over diarrhoea, outbreaks are increasingly difficult to detect using traditional methods. This hides the true burden of disease.
Professor Sarah O’Brien at the University of Liverpool and her collaborators will use data from multiple sources to scout for infection in the community, take samples and analyse them, using modern technology to detect organisms. The researchers will analyse the DNA of microbes to discover which family of organisms they belong to and how they are evolving. Since many diarrhoeal diseases can pass between humans and animals the project team will develop and integrate veterinary and medical surveillance.
The ultimate goal is an integrated real-time, surveillance/diagnosis/investigation system - centred on the patient - that detects community outbreaks sooner, enables Health Protection professionals and Environmental Health Officers to intervene quickly and thus lessen short- and long-term harm.
Implementation of microbial whole-genome sequencing for individual patient care, local outbreak recognition and national surveillance
Rapid, next-day access to information regarding micro-organism species, drug resistance, and relatedness would be an unprecedented advance for infectious disease treatment and control.
The existing multiplicity of disconnected pathogen-specific systems make fast, cheap and comprehensive characterization impossible. However, such information could be deduced from whole-genome sequence analysis of the disease-causing microorganisms.
Professor Derrick Crook at University of Oxford and his collaborators propose to translate whole-genome sequencing into routine clinical microbiological practice. The goals of their 3 year programme are to demonstrate locally-based genome sequencing operating in a network of routine NHS service laboratories at Oxford, Brighton, Birmingham and Leeds.
This will serve as a model for a national surveillance system and a faster, more informative alternative to centralized reference facilities for infection prevention and control. Currently analysis of a single clinical sample may take days-to-months. The aim is to provide complete pathogen information within 24 hours of culture, linked to a national surveillance database thereby enabling more timely and better targeted patient treatment.
Translating whole genome sequence technology into diagnostic and public health microbiology
Effective mechanisms of surveillance are required to track disease trends, identify new infectious disease threats, detect serious outbreaks, monitor control measures, design effective vaccines and monitor for vaccine escape. The present public health system falls short of what is required because of a technology gap whereby it is not possible to make rapid or in some cases accurate inferences regarding pathogen outbreaks and transmission events using the currently available microbial genotyping methodology.
Through this award to Cambridge University, Professor Sharon Peacock will seek a solution to this need through the development of a world-class system of active surveillance based on microbial whole genome sequencing (WGS), in collaboration with the Cambridge University Hospitals NHS Trust, the Health Protection Agency and the Wellcome Trust Sanger Institute.
The aim is to embed a genome sequence-driven microbiology initiative within a clinical campus, working alongside a hospital diagnostic and public health laboratory. Key objectives are to understand how to apply genomics to address the problems of infectious disease control scaled to local, regional or national levels, and how to integrate this technology into on-going practice so as to expand and enhance the current system of infectious diseases surveillance conducted.
Infection response through virus genomics
Viruses are a major cause of morbidity and mortality, with a high cost to the NHS. Viruses have significant genomic variation, which underpins pathogenicity, drug resistance, and transmission.
Despite enormous advances in technology, we currently lack the systems, facilities and capacity to routinely capture full-length viral gene sequences, to monitor drug resistance at the granularity to optimally guide treatment, to identify the source of viral transmissions within healthcare settings, and to track emerging epidemics.
Professor Deenan Pillay at University College London and collaborators are developing next generation sequencing technology to capture virus genomes from clinical samples. The team’s goals are to i) deploy optimal methods for preparing clinical and surveillance isolates for sequencing, ii) develop robust and reliable real time full length virus sequencing, iii) deliver data to NHS users in a form suited to inform direct clinical care, hospital control, and intervention in epidemics.
It is hoped that the technology will lead to more effective treatment of HIV and HCV infections, more targeted hospital infection control regarding norovirus infections, and better dynamic assessment and targeted management of community based viral outbreaks, in particular measles and influenza.
Translation of non-invasive prenatal diagnosis (NIPD) for selected single gene disorders into a clinical setting
Current prenatal genetic testing is by amniocentesis or chorionic villus sampling which each carry miscarriage risks. Recently developed tests, called “non-invasive” prenatal diagnosis (NIPD), do not have miscarriage risks.
These are possible since the discovery that there is a small amount of a baby’s genetic material, known as free fetal DNA, present in a pregnant mothers blood. Tests for some genetic disorders, such as the muscle disorders Duchenne and Becker muscular dystrophies are currently being developed. However because there are thousands of different genetic disorders, many extremely rare, it is challenging to make these tests available to a wide range of different families.
Scientists must show that the NIPD tests are accurate on stored blood samples for a range of conditions and then show that the tests are possible in the antenatal clinic and provide the same accurate results. Once proven the tests can be considered by the UKGTN (UK Genetic Testing Network) for implementation into routine NHS service.
This project led by Dr Stephanie Allen of the West Midlands Regional Genetics Service aims to accelerate the safe transfer of genetic research into improved patient care for many different genetic disorders. Removing the miscarriage risk with the introduction of NIPD will increase the acceptability, and therefore availability, of prenatal genetic testing for many couples.
Gene therapy for blindness caused by choroideraemia: a Phase I clinical trial
Professor Robert MacLaren and colleagues from University of Oxford are undertaking a clinical trial using gene therapy to treat a disease that causes blindness known as choroideraemia. This condition is currently incurable and affects thousands of people worldwide.
The principle of gene therapy is to use the shell of a virus (known as a vector) to carry a segment of DNA into the cells of affected patients where it can have a beneficial effect. In the case of choroideraemia there is deficiency of a gene known as REP1.
The project team have put this gene into a viral vector and shown in their laboratory that it can correct the choroideraemia defect. The project has reached the point where the team are ready to assess the potential benefit of this treatment in patients. Professor MacLaren and colleagues have designed a study involving 12 patients across four NHS sites that would represent the world's first ever clinical trial for this disease. The effects of the gene therapy will be assessed two years after treating each patient. If these are shown to be successful, subsequent regionally located follow-on studies will be set up.
Advanced antisense oligonucleotide technology for exon skipping in Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is the most common lethal variant of muscular dystrophy, and affects 1 in every 3500 live male births or 250,000 people world-wide.
Recent encouraging clinical trials have used antisense oligonucleotides (AOs) which, like 'molecular velcros', are able to temporarily repair the mutated DMD gene and restore the lost dystrophin protein to the muscles of DMD patients. However this approach requires repeated administration of the AO drug in order to achieve some repair of the gene in the skeletal muscle; in addition the heart muscle cannot be targeted efficiently with the current AO chemistries.
New generation AOs, never tried before in the human, are able to dramatically improve skeletal and cardiac muscle uptake of these molecules in animal models of DMD and significantly improve their therapeutic efficacy. In this study the MDEX Consortium, a world-leading group of preclinical scientists and clinicians based in the UK developing state-of-the-art therapies for neuromuscular disease plans to focus on the development and optimisation of a safe new generation AO drug which we intend to administer to a group of 9 patients affected by DMD after appropriate safety studies. The project is being lead by Dr Matthew Wood, University of Oxford and Dr Francesco Muntoni, UCL Institute of Child Health.
Using pharmacogenetics to improve treatment in young-onset diabetes (UNITED)
Monogenic diabetes is an unusual form of diabetes. It usually presents in patients under the age of 30, so is often misdiagnosed as Type 1 diabetes which is more common. Patients with monogenic diabetes can often be treated with tablets rather than insulin injections, leading to better control of their diabetes, and fewer side-effects and complications. Less than 5% of people with monogenic diabetes in the UK have been identified, meaning up to 20,000 patients may still be misdiagnosed and receiving inappropriate treatment.
The aim of project 'UNITED' is to identify the prevalence of patients with monogenic diabetes resulting from mutations in the HNF1A, HNF4A, or GCK genes, amongst patients with early-onset diabetes, diagnosed at less than 30 years of age. A team led by Professor Andrew Hattersley of the Peninsula Medical School and University of Exeter aims to develop a health economic model of a care pathway leading to the testing of monogenic diabetes.
This will help to identify the best way of ensuring that people diagnosed with diabetes under the age of 30 have all the necessary tests to ensure they have the correct treatment for their particular type of diabetes. A small number of people may, as part of this study, be found to have a specific genetic cause of their diabetes and, in these cases, the success and benefits will be measured of changing their treatment, usually from insulin to sulphonylurea tablets.
Deciphering developmental disorders
Thousands of babies born each year in the UK fail to develop normally because of errors in their genetic makeup. Currently, diagnosis is restricted to a small minority of children and requires the clinician to recognise the appearance of the child and the pattern of symptoms, supplemented by the use of microscopes to identify large rearrangements of the genetic material in chromosomes.
Research shows that the latest molecular testing methods identify previously undetectable changes in chromosomes allowing new diagnoses to be made. However, clinical use is hampered by the limited availability and inconsistent application of these technologies, and by lack of basic knowledge to link genetic changes directly to symptoms. The consequence is that clinical diagnoses remain impossible except for a small number of children.
Dr Nigel Carter of the Wellcome Trust Sanger Institute and colleagues propose to apply state of the art genetic sequencing and molecular testing to 12 000 UK children with abnormal development. The results will provide a unique online catalogue of genetic changes linked to symptoms that will enable clinicians to diagnose developmental disorders. Furthermore, they will design more efficient and cheaper diagnostic assays for relevant genetic testing to be offered to all such patients in the UK and so transform clinical practice for children with abnormal development.
Quantifying disease burden in patients with cancer using tumour-specific genomic rearrangements
Cancer is caused by the accumulation of genetic damage (mutations) in cells within a particular organ. These mutations are only found in the cancerous cells and therefore could be used to track the malignancy during treatment. Advances in DNA sequencing allow the high-throughput identification of these mutations from any cancer sample in a clinically relevant time-frame. As tumour cells die, they release their DNA into the bloodstream.
Dr Peter Campbell, Wellcome Trust Sanger Institute and colleagues propose to use the new generation of genetic sequencing technologies to identify a particular class of mutations caused by the abnormal rearrangement of chromosomes in patients with breast cancer and colorectal cancer. From these rearrangements, the team will develop assays to detect DNA from each patient's cancer that has been released into the bloodstream. Such assays will be highly specific (minimal risk of falsely positive results) and sensitive (capable of detecting one copy of tumour DNA in many millilitres of blood).
The programme will measure the amount of disease using blood samples collected before surgery, after surgery, during chemotherapy and at regular time-points post-therapy. Dr Campbell and colleagues will therefore be able to assess the ability of this approach to identify high-risk patients before treatment begins, to monitor response to treatment and to predict cancer relapse before it is clinically apparent.
Efficient intraoperative detection of tumour margins through X-ray phase contrast CT
Many breast cancer patients undergo operations that are local excisions to remove the cancerous tissue rather than the entire breast. This has advantages but also risks. To minimise the risks of tumour recurrences, the surgeon must remove a margin of healthy tissue from around the cancer to provide a sufficient safety margin. The tissue sample is then analysed to ensure the whole tumour has been removed. It currently takes about ten days to test that the surgeon has removed enough tissue, leading to a delay in women knowing whether they will need another operation. It would be a huge advantage to the surgeon to know quickly and accurately whether the safety margin is adequate.
Ian Haig from Nikon Metrology UK proposes using a new X-ray imaging method invented by his project partner, Professor Alessandro Olivo at University College London. The method uses refraction instead of attenuation to detect small tissue changes, such as tumours. The technique has already detected tumour features missed by other technologies.
This award will allow the team at Nikon, University College London and Queen Mary University of London to build and validate a scanner that visualises the tissue safety margin in minutes, and is compact enough for use in an operating theatre. This will allow ‘intra-operative’ use, so that a surgeon will know whether the safety margin is correct while the patient is still on the operating table. It is hoped this new technology will significantly reduce breast cancer recurrence and avoid the cost and distress of repeat operations.
Development of a synthetic bioactivated membrane dressing
Scarring impacts many patients, for example by reducing movement of the limbs or even making people blind. Scars are also often unsightly, sometimes causing psychological problems. When wounds such as burns are treated, the main priority is to stop dehydration and infection; no dressings are designed to actively prevent scar formation.
A research group headed by Professors Ann Logan and Liam Grover at University of Birmingham has invented membrane technologies that can incorporate a molecule that is one of the body’s natural protections against scar formation, called Decorin. They have shown that this molecule, delivered from a membrane wound dressing, can stop formation of scars in the lab.
In this project, they will demonstrate that the new anti-scarring dressing is successful in both animals and humans. Importantly, they will make sure that the technology can be produced in large quantities that behave in a predictable way, so that it could be turned into a medical product and used in the clinic. The resulting medical product will help to improve the quality of life of many patients who have been injured in a way that would normally result in scarring. If this new dressing is successful in treating burns it could also be used in many other applications where scarring is a problem.
Tissue oxygen monitoring for detecting impending shock states and guiding therapy in the critically ill and those at high-risk
Complications frequently occur following trauma, infection and major surgery. This can lead to failure of organs (e.g. lung, kidney, gut) necessitating admission to intensive care for organ support. Mortality rates are high and long-term disability common in survivors.
Studies already show how early resuscitation of the circulation in these patients can considerably improve outcomes. Although it is possible to gauge how much blood the heart is pumping to the tissues (cardiac output) better bedside monitors are needed to assess if the cardiac output is actually adequate for perfusing the organs.
Patients who are unwell or undergoing major surgery routinely have a bladder catheter placed to drain urine. Dr Andy Obeid of Oxford Optronix Ltd, together with Professor Mervyn Singer at University College London, plan to use this catheter to co-insert a small, flexible fibre-optic based sensor to continuously monitor oxygen levels within the bladder wall. This device will indicate whether or not the local blood supply transporting oxygen to the bladder is indeed adequate and whether oxygen measurements from the bladder reflect the situation in other parts of the body.
Their aim is to assess whether this new technology provides an easy and readily applicable solution to monitoring tissue health during acute injury. This will pave the way for a further clinical investigation in which the circulation is optimised using the device to see if a reduction in post-trauma complications can be achieved.
Totally automated blood pressure monitoring at home to improve care of patients with Heart Failure or Pulmonary Hypertension
Many older people suffer from the long-term disabling illnesses of heart failure and/or pulmonary hypertension. The symptoms are shortage of breath and severely restricted walking range. Without medication, patients get progressively worse until the disease kills them. With medication - a combination of three types - the symptoms can be successfully alleviated. Both over-medication and under-medication can be medically dangerous and costly, either a waste of drugs, side effects or the patient requiring re-hospitalisation.
The vital measurement for controlling medication is pulmonary artery pressure (PAP) which currently can only be measured by catheterisation, involving a hospital procedure and some risk. Professor Chris McLeod and colleagues at Imperial College London have developed a tiny pressure sensor with which they propose to measure PAP. Once the device is placed securely within the artery, measurements can be made at any time by interrogating the sensor by radio from a pocket-sized reader. The reader will be permanently and wirelessly linked to the hospital.
Professor Tarassenko's research group at Oxford University will apply its extensive technical and clinical experience of real-time monitoring of patients in hospital and of the use of mobile-phone based telehealth to improve the management of chronic disease. Close control of the medication will be possible, leading to improved patient condition, slower progression of the disease and reduced re-hospitalisation. Measurement quality is guaranteed and measurements during normal activity will be better than current catheter-based measurements in a clinic or hospital bed. The patient will know that they have 24/7 care.
Real-time detection of the onset of secondary brain injury in the intensive care unit
Traumatic Brain Injury (TBI) - a major cause of death and disability in all age groups, and the most important cause of these outcomes in working people, is now recognised as a ‘silent epidemic’ in the United Kingdom and worldwide. Central to TBI’s devastation is a delayed ‘secondary’ injury that occurs in 30% of TBI patients each year, while they are receiving Intensive Care. Currently, secondary injury is unpredictable, hence unpreventable.
This project, led by Dr Martyn Boutelle of Imperial College London, will deliver a new solution: a real-time Brain Injury Index. This will be produced with a new clinical instrument that will collect electrical and chemical signals from the injured brain, process them and for the first time derive clinically useful risk factors in real-time that will assist doctors with diagnosis and treatment.
The healthcare implications are important: The Brain Injury Index will show clinicians when secondary damage is starting and what is causing it. This will allow them to start the best treatment for that patient at the right time. The Brain Injury Index instrument will save lives, and reduce incidences of severe disability with its huge personal cost to patients and their families.
Viability testing and transplantation of marginal livers
Liver transplantation is the only therapeutic option for patients with end-stage liver disease. There are two types of cadaver organ donors: donation following brain death (DBD) and donation following circulatory death (DCD). The latter are from patients with no prospect of recovery who have supportive treatment withdrawn. In DCD, the organs are exposed to an additional warm period without oxygen and so recipients have a higher risk of graft failure or complications. DBD donation is decreasing, so DCD organs are a vital source. However a significant number are rejected due to their poor condition.
Normothermic machine liver perfusion (NMLP) is a technique by which a liver is perfused with a combination of blood and other fluids at the body's normal temperature. It aims to mimic the environment that a liver experiences in the body. Professor Darius Mirza and colleagues at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust have discovered a technique that uses NMLP to enable clinicians to test the viability or function of the organ before transplantation. This may reduce the risk of primary non-function for patients. This additional feature may also facilitate safer use of higher-risk organs. The key objectives of the research are to validate the protocol for viability testing of discarded donor livers, and increase the number of livers available for transplantation.
Characterisation of cell types obtained from mixed cell cultures of the human olfactory mucosa, for the application of central nerve repair
Spinal cord and root injuries are commonly due to road traffic accidents and can result in permanent paralysis with major physical, psychological and economic impacts. Although surgical repair of spinal root and cord injuries can restore some movement, patients seldom report good functional outcome.
Olfactory ensheathing cells (OECs) are a promising cell candidate for nerve repair and can be obtained from the olfactory mucosa of the nose, where they normally induce repair of damaged olfactory nerve fibres for the sense of smell. They can be obtained by a simple biopsy of the olfactory mucosa using an endoscope.
Through funding from the Health Innovation Challenge Fund, Mr David Choi and colleagues at UCL aim to better understand the cell quality attributes and final product formulation to ensure a robust, well-characterised cell product that is effective in laboratory assay systems and satisfies regulatory requirements. With this information the team can then proceed with production of cells for transplantation and plan to start a phase 1 clinical trial involving transplanting a patient's own OECs during the surgical repair of brachial plexus avulsion, within three years. Positive results would impact not only patients with brachial plexus injuries, but also patients with spinal cord injury or stroke.
Magnetic resonance guided ablation system for treatment of ventricular tachycardia
Ventricular tachycardia (VT) is a form of cardiovascular disease where patients suffer from a dangerously fast heart rhythm. This results in a reduced pumping capacity of the main heart chambers, the ventricles, and is the leading cause of sudden cardiac death. The occurrence of VT is related to scar tissue formation in the heart muscle.
VT is treatable using minimally invasive surgery with ‘ablation’ technology. Treatment involves destroying the abnormal scarred regions of heart muscle, this is accomplished using a catheter to deliver energy at the treatment location. The current success rate is around 50%: as a result patients still frequently require a defibrillator (ICD), an expensive implanted device that shocks the patient back into a normal rhythm. These shocks are unpleasant and impact both patient quality of life and long term survival.
This study aims to use magnetic resonance imaging technology (MRI) to improve VT ablation accuracy by allowing direct visualisation of the scar that causes the VT. With improved ablation outcomes and higher success rates, fewer patients would receive frequent ICD shocks, and in the future it may even be possible to avoid implantation of an ICD altogether.
Professor Reza Razavi’s team at KCL have developed a prototype system for treating irregular heart rhythms (arrhythmias) inside an MRI scanner and have shown in a first-in-man study that it is possible to treat simple arrhythmias using the MRI images. Application of this technology to treat VT will enable a more detailed analysis of the cause of the VT, improved targeting of the treatment and more rigorous assessment of treatment results, greatly improving patient outcomes.
Bioactive nanofibrous sutures to enhance endogenous repair of rotator cuff rears
Rotator cuff tendon tears are very common and are found in around 15% of 60 year olds, 25% of 70 year olds and 30% of 80 year olds. Tendon tears often cause significant pain and loss of function and present a substantial and growing social and economic burden. Many patients are unable to work effectively due to their symptoms and pain which significantly disrupts their sleep is common. Unrepaired tears grow in size and very large tears are associated with joint failure and the development of secondary osteoarthritis. In patients with persistent symptoms surgical repair is commonly performed.
Professor Andrew Carr at the University of Oxford is developing is a novel suture material (Bioyarn) that is designed to stimulate repair when in contact with the torn and damaged tissue. Bioyarn is constructed of biodegradable electrospun polymeric nanofibres and is designed and manufactured to mimic the architecture of normal tendons. Studies have demonstrated that the new material stimulates cell growth and new tissue formation, and has a good safety profile. The aim is to further evaluate the technology and undertake a clinical study in humans to examine how effective the Bioyarn technology is at increasing the success of rotator cuff tendon repairs.
Image-guided neurosurgical treatment of epilepsy
One third of individuals developing epilepsy are uncontrolled with medication. If epilepsy arises from one part of the brain, surgical removal of this area can be curative. This needs to be balanced by the risk of causing new deficits such as paralysis or impaired speech. Improved diagnostic methods, and surgical precision, will improve the benefit/risk ratio of epilepsy surgery, and increase treatment availability.
At University College London, teams led by Professor John Duncan and Professor Sebastien Ourselin have developed software to visualise the whole range of 3D brain imaging, including normal architecture, abnormalities of structure and function, arteries, veins, critical brain areas and nerve pathways, and the skull. This increases the safety and precision of implantation of the electrodes necessary to pinpoint the brain tissue that needs to be removed to cure the epilepsy.
This project aims to implement automated planning of electrode trajectories and robotic systems for placing the electrodes into the brain. It will also establish methods for automated 3D planning of neurosurgical resections, so that surgery is optimal and quicker. Consequently, curative neurosurgery will be available more quickly to more individuals. The surgical advances pioneered here will be applicable in future to other procedures, such as taking biopsies and tumour surgery.
Note this is a HICF award but funded solely by the Trust as a Translation Fund project.
Micro-IGES – Microscopic Image Guided Endoluminal Surgery
The current surgical technique for removing cancer from the body is generally effective, however it carries a significant risk to patients during surgery and long-term post-operative problems such as chronic pain, disfigurement and poor quality of life.
Early stage cancer within a lumen, such as the colon, and precancerous polyps, can be removed endoscopically, thus avoiding the need to make a large incision on the body and potentially the creation of an artificial opening from the colon through the abdominal wall (colostomy). However, with the current instrumentation design, even tumours close to the external orifices of the bowel are difficult to remove with absolute certainty of completion.
A project team led by Professor Guang Zhong Yang and Professor Ara Darzi at Imperial college are developing a robotic surgical device to facilitate tumour removal without the need for invasive surgery. Micro-IGES provides a novel microscopic surgical platform with a greater degree of precision and accuracy through integrated sensing, probe-based microscopic imaging and robotically assisted intra-operative guidance. The platform will be evaluated in both in-vivo animal models and human clinical studies.
Perfecting soft tissue attachment interface to an osseointegrated transdermal implant to deliver a predictable and robust patient outcome
About 5000 new amputees each year are referred to limb fitting centres in the UK. Traditionally amputees attach their artificial limb using a socket that fits onto the limb stump. Often attachment is cumbersome, uncomfortable and restricts daily activities.
In addition, the stump does not effectively transmit load and control movement. This causes tissue problems, which means that patients must frequently visit clinic and sometimes the artificial limb is not used due to discomfort. These long-term problems are a burden on the NHS and reduce amputees' quality of life.
The ITAP system being developed by Paul Unwin and colleagues at Stanmore Implants Worldwide Ltd uses an implant attached to the bone that projects through the skin, to which the artificial limb is easily attached. This arrangement transmits load through the skeleton, which is how loads are naturally transferred. The success of the ITAP implant is reliant on the integration of the skin around the implant to create a seal to prevent infection. The objective of this programme is an implant that provides patients with an effective solution for the attachment of artificial limbs.
SmartTarget: Image-guided diagnosis and treatment of localised prostate cancer
In current practice, the prostate cancer pathway is often compromised by lack of information on tumour location. This leads to ‘blind’ biopsies causing under-diagnosis of clinically important cancer, over-diagnosis of clinically unimportant cancers and poor risk-stratification. As a result, once diagnosed men usually undergo whole-gland treatments that confer significant rates of incontinence, impotence and rectal toxicity due to collateral tissue damage.
Research led by Professor Mark Emberton and Dr Dean Barratt at University College London (UCL) seeks to rectify this situation. Their project proposes to combine state-of-the-art diagnostic imaging with advanced image guidance technology so that doctors are provided with information on cancer location, shape, and size during surgical procedures. The aim is to transform prostate cancer care by enabling doctors to target clinically important cancers so that these are diagnosed more accurately.
The project focuses on developing a novel device called “SmartTarget” which will ensure that information on the location of cancer from medical imaging is at the centre of the diagnosis and treatment of prostate cancer. The SmartTarget device will exploit magnetic resonance imaging (MRI), which can detect clinically important cancers more accurately, and translate information on cancer location, size and shape automatically into the surgical setting. The device aims to achieve this by presenting the doctor with a “picture” that combines information from MRI with information from ultrasound images that are widely used to guide the biopsy needle and treatment delivery. This will allow the doctor to identify and target the cancer on a computer screen in a similar way to a fighter pilot presented with a target on a head-up display.
Anticipated benefits of this technology include fewer biopsies and more accurate cancer diagnosis. The ability to implement a more selective treatment strategy will result in less harm and cost significantly less than current strategies which treat the whole prostate gland. The specific objectives of the project are to develop and test the prototype SmartTarget device on patients, to develop detailed plans to commercialise the device, and to introduce the technology within the NHS (and potentially other healthcare systems) within a 5 year period.
Novel multimodality imaging techniques for neurosurgical planning and stereotactic navigation in epilepsy surgery
Successful neurosurgery for epilepsy depends on removing the parts of the brain that give rise to seizures, and avoiding damaging areas undertaking vital functions such as language, movement and vision. Current techniques to direct surgery are based on MRI scans to show brain structure, but do not show areas needed for vital tasks, and do not permit interactive simulations of placement of recording electrodes in the brain.
A research group headed by Professor John Duncan at University College London and Dr Sebastien Ourselin of UCL Centre for Medical Image Computing has implemented methods to identify critical areas of brain function, connections and blood vessels and display these in 3D.
They plan to develop this system to enable the neurosurgeon to plan the best operative approach for inserting recording electrodes and for planning surgical resections. This information will be made available in the MRI scan guidance system in the operating room so that operations are more precise. They will produce a new system that will result in epilepsy surgery being planned more effectively, resulting in a higher cure rate and fewer complications.
Smart laparoscopic liver resection: integrated image guidance and tissue discrimination
Liver cancers can be removed using key-hole surgery with less pain, tissue damage, and blood loss and faster recovery times than traditional open surgery. However few cancers are removed by this method because of the difficulty in identifying and dividing blood vessels within the liver using key-hole surgery techniques. In addition, the position of the tumour and major vessels in the liver alters during the surgery due to patient breathing and liver traction.
A research group headed by Professor Brian Davidson and Professor David Hawkes at University College London proposes to use the CT scan taken prior to surgery to identify the precise location of the cancer to the surrounding vessels and bile ducts and hence build a computer model of the liver for each individual patient. They will use this to monitor the position of the cancer and the major structures to the liver during the course of the key-hole surgery. This will be combined with a new method of detecting what kind of tissue is directly in front of the cutting instrument.
This system is likely to result in a significant increase in the proportion of patients who undergo liver resection using key-hole surgery. The system will be validated on pigs and then evaluated on at least 25 patients. The system developed will also be applicable to operations on the pancreas, kidney and gallbladder.
A new minimally invasive surgery for the treatment of corneal endothelial disease
The cornea is the transparent tissue at the front of the eye which allows light to reach the retina. If the cornea becomes cloudy, vision is impaired, a bit like looking through a frosted glass window.
Often the only treatment is a cornea transplant in which a surgeon removes the damaged cornea and replaces it with a donor cornea or part of a donor cornea. Often this has a good outcome, but the number of donor corneas available for surgery is limited, and risks such as infection or rejection remain.
Professor Andrew Quantock’s team at Cardiff University together with collaborators at Kyoto Prefectural University of Medicine and Doshisha University in Japan plan to develop a new surgery for corneal cloudiness which is caused by diseased or damaged cells that line the inside of the cornea. Under local anaesthetic, they will very gently touch the front of the cornea for a few seconds with a new surgical device which very quickly freezes cells. In doing so the diseased endothelial cells at the back of the cornea are destroyed. The researchers will then apply eye drops which will encourage healthy endothelial cells to grow and repopulate the inside of the cornea. In this way the cornea can become healthy and clear again.
Topical delivery of Ranibizumab for non-invasive treatment of retinal disease
Age-related macular degeneration (AMD) is a major cause of blindness, affecting 30-50 million people worldwide, with a rising incidence due to the rapidly increasing ageing population.
Current treatments – of which Ranibizumab is the most frequently prescribed – involve monthly injections into the eye to block a protein known as vascular endothelial growth factor (VEGF) which is responsible for new blood vessel formation. The injections require specialist administration at clinics and cost £85 million per year in the UK which is a high burden for the NHS. There is a clear, unmet need for anti-VEGF treatments to be non-invasive, easy to administer and less expensive.
Professor Francesca Cordeiro and her team at University College London have developed a formulation that can be used to replace monthly hospital-administered intraocular anti-VEGF injections with daily self-administered eye drops. This project aims to optimise the formulation for Ranibizumab, develop its manufacturing process, and assess its safety and tolerability to enable it to be tested in first-in-man clinical trials. If successful, the Ranibizumab eye-drop will lead to widespread treatment programmes that have the potential to reduce the burden of AMD on the individual and society by changing the way treatment is delivered.