Grants awarded: Pathfinder Awards

Project summaries of Wellcome grants awarded under the scheme ‘Pathfinder Awards’.

Medical devices

IMage-guided Pancreatic Ablation for Cancer Therapy (IMPACT)

In the UK, 8,773 people were diagnosed with pancreatic cancer in 2011 and there were 8,662 deaths from the disease in 2015. It is a biologically aggressive cancer, which is resistant to chemotherapy and radiotherapy and has a high rate of recurrence. Surgical resection remains the only treatment with potential for long-term survival and cure. However, many patients have metastatic disease at presentation and a third have locally advanced pancreatic cancer, leaving only 10-20% of people with the disease suitable for potentially curative resection. Even after resection, recurrence is common leading to an overall five-year survival ranging from 7-25%, with a median survival of 11-15 months. Adjuvant chemotherapy is beneficial but still only delivers a median survival of between 14-24 months. In people who do not undergo resection, the median survival is only about 8-9 months. Thermal ablation, which is established for palliation of other cancers, is not recommended for unresectable pancreatic cancer because of the risk of injury to the pancreatic duct resulting in acute pancreatitis and fistulae and the proximity to major blood vessels including the portal vein and aorta which may be damaged and which also drain heat making the procedure ineffective.

This project will develop a patient-specific planning, simulation and intra-operative navigation system for individualised ablation and palliation of inoperable pancreatic cancer. Dr Danail Stoyanov and colleagues at University College London will investigate a new technique – irreversible electroporation ablation (IRE) – which causes cell death through a different mechanism to thermal ablation and can minimise damage to the pancreatic duct and major blood vessels. To be effective IRE needle electrodes must be accurately positioned in the pancreas. There is currently no way of placing the IRE electrodes to achieve this accurate placement of electrodes. The proposed navigation system will address this problem so that electrode placement can be carried out percutaneously or under laparoscopic guidance. We will develop the navigation system, test it in animal experiments and prepare a first-in-man clinical trial. 

The results of the project have the potential to prolong and increase the quality of life for a patient population with dismal prognosis and limited treatment options.

A device for the removal of circulating autophagic vesicles in patients with sickle cell disease

Sickle cell disease (SCD) is now the commonest inherited genetic disorder in the UK with a total of 14,000 patients and more than 300 children with the condition born each year. There are three available disease-modifying treatments available: hydroxyurea; blood transfusion; and stem cell transplant. Transfusion remains the mainstay of preventive treatment and is the only validated treatment for stroke prevention. People with SCD accumulate more comorbidities as they age and about 40% of children with SCD have clinical evidence of stroke by school age. Despite the success of regular transfusion there are clinical situations where transfusion may be unsuitable, unwanted, unavailable or insufficient. 

Dr Sara Mole, University College London, aims to develop a method for the selective removal of circulating phosphatidyl serine-exposed ‘inside out’ autophagic vesicles from the plasma of patients with SCD. We will exploit monoclonal antibodies directed at epitopes located on the cytoplasmic domains of proteins expressed on the red cell membrane to develop an immunoaffinity column suitable for clinical use. This technology will have life-changing and life-saving effects by offering a therapy that does not use donated red cells. There are frequent clinical scenarios where people with severe SCD who need transfusion are not able to have one because blood is not available in sufficient quantity on a regular basis or it is not available at all. This includes patients with a complex mixture of alloantibodies as a result of previous transfusions and patients with ongoing active disease despite transfusion. The latter group of patients often have single organ damage such as progressive renal vasculopathy or cerebral vasculopathy and currently there is no further treatment option available for them. About 90% of patients with SCD live in the developing world where there is no safe and freely available access to blood. A therapy that did not require blood products would be highly desirable. 

We anticipate that the selective removal of circulating autophagic vesicles from the blood of SCD patients will greatly reduce vasculopathy and result in a dramatic improvement in quality of life for people with SCD.

Strengthening the neuromuscular junction as a new concept for the treatment of congenital myasthenic syndromes and motor neuropathies with synaptic dysfunction

Disruption of the development and maintenance of the neuromuscular junction (NMJ), through mutations in the genes encoding its components, lead to congenital myasthenic syndromes. These disorders result in impaired neurotransmission and muscle weakness. The phenotypical spectrum of NMJ dysfunction is expanding; several recently identified mutations in presynaptic NMJ proteins have been shown to cause hereditary motor neuropathies, and NMJ abnormalities have been demonstrated in genetic neuropathies. Current treatments for these conditions are limited in that they are mainly symptomatic and have side-effects.

Development and maintenance of the NMJ depends on the neuronal factor agrin and the agrin/LRP4/MuSK pathway. The naturally occurring form of agrin is highly insoluble and its activity is counteracted through cleavage by the neurotrypsin protease. Neurotune AG, a Swiss biotech company, has developed a modified form of agrin (NT-1654) which is soluble and resistant to proteolysis.  

Professor Hanns Lochmüller and colleagues at Newcastle University will be testing NT-1654 in mouse models of human congenital myasthenic syndromes and hereditary motor neuropathies. The team aim to provide evidence that NT-1654 improves neuromuscular transmission in these models. Their goal is to identify improved molecular mechanisms and provide evidence for NT-1654 usage as a therapeutic reagent in clinical trials.

Development and assessment of a novel intra-luminal sensor for monitoring intestinal viability in colorectal cancer surgery

Bowel surgery is still the only reliable cure for bowel cancer. After cancer removal, the cut ends of the bowel are joined together to form a ‘bowel joint’ called an anastomosis so patients can still empty through the back passage.  In 2-20% of patients, the anastomosis does not heal, leaking bowel contents inside the abdomen, which can lead to death. Reduced blood flow at the anastomosis is an important reason for leakage. At present, there is no simple technique to identify the problem early. 

This project, led by Professor Panayiotis Kyriacou at City University of London, aims to develop a new device capable of providing continuous measurements of blood flow, and other key parameters from the bowel tissue. The new device will allow the surgeon to predict the health of the anastomosis and help to identify leakage and the significant harm associated with it. If successful, the device could be used routinely in gastrointestinal surgery, improving patient safety and reducing treatment costs.

Manufacture and testing of clinical prototypes of magnetic blood filtration device to treat malaria

MediSieve is developing a novel magnetic blood filter device to treat malaria, with a focus on severe and drug resistant patients. In a process similar to dialysis, a patient's blood is continuously circulated through the device via an external blood loop. Malaria infected cells are captured and removed by exploiting their naturally occurring magnetic properties, while the rest of the blood returns to the patient unaffected.

The magnetic blood filter can deliver a very rapid reduction in a patient's infection burden to improve survivability and recovery times. It can be used as a standalone treatment for currently untreatable patients (drug resistant cases, pregnant women etc.), or in combination with drugs or order to improve their efficacy. By removing rather than killing infected cells, the magnetic filter avoids many of the undesirable side-effects of drug treatments.

This Pathfinder Award will enable MediSieve to develop clinical prototypes of the filter, and perform safety testing to demonstrate that the procedure does not cause any harm to healthy blood components. By the end of the project Medsieve aims to be in a position to apply for approval to perform clinical trials.

A synergetic adaptive non-intrusive-navigation assistance system for empowering the disabled, elderly and infirm powered wheelchair user

Many powered wheelchair users find their medical condition and their ability to drive the wheelchair will change over time. For example, those with Multiple Sclerosis or Motor Neurone Disease will progressively lose their ability to drive safely. In order to maintain independent mobility the powered chair will require adjustment over time to suit the user's needs.

Currently, this need for regular input from the healthcare professional, and the limited resources, can result in the user having to wait weeks for appointments. This results in the user losing independent mobility for significant periods of time, consequently affecting their quality of life and that of their family and carers.

Research by Dr Gareth Howells at the University of Kent has led to the development of an assistive navigation system which helps the powered wheelchair user manoeuvre through doorways and avoid obstacles. This novel method can be adjusted to an individual’s requirement changes over time. Therefore this project will obtain user data from a range of users’ changing abilities over time in order to provide data for adjusting the assistive system. In addition the practical usability of the existing navigational assistive prototype will be investigated by users in the real world environment in order to establish the proof-of-concept system’s ability to offer practical assistance to real users.

Localization of arrhythmogenic foci with a radio-frequency atomic magnetometer

Atrial fibrillation (AF) is a poorly understood arrhythmia which affects 3-5% of the population over 70. A significant challenge for treatment is identifying the precise localization of arrhythmogenic foci in the atria or ventricles. Localization of arrhythmogenic foci for ablation treatment requires creating a conductivity map of the heart, which involves an invasive and prolonged surgical procedure.

Due to time and resource issues, AF ablation is currently under delivered in the UK with approximately 2000 procedures in 2010, whilst the expert UK consensus is for a minimum of approximately 6000 per year. AF ablation success rates are also lower than desired because of difficulty locating the arrhythmogenic foci, with a success rate of ~60-70% for the first procedure, which rises to 90% for a second procedure.

This Pathfinder Award supports a partnership between Dr Witold Chalupczak at the National Physical Laboratory (NPL) and Professor Ferruccio Renzoni at University College London (UCL) to investigate the use of magnetic induction tomography (MIT) to perform conductivity mapping of the heart. This MIT mapping will occur through the use of an ultra-sensitive, radio-frequency magnetometer which will be developed and tested during the project. This technology would enable high resolution non-invasive magnetic imaging of the heart and would offer the opportunity to avoid prolonged invasive mapping of arrhythmias prior to ablation, while facilitating pre-operative planning of treatment.

Reanimating faces: Creating an iPad/mobile device application to facilitate rehabilitation following Bell's Palsy

A Pathfinder Award facilitating the new partnership between Image Metrics Ltd with Queen Victoria Hospital NHS Foundation Trust and Aesthetic Research Group LLP. Bell’s palsy affects approximately 25,000 people in the UK each year and leaves up to a third of them with chronic facial disfigurement.

Image Metrics Ltd, leaders in facial movement tracking and animation for the film and gaming industry have teamed up with Mr Charles Nduka, a reconstructive plastic surgeon specialising in facial paralysis treatment to develop a novel home-based facial movement tracking and rehabilitation app. In this collaboration with sensor technology company, Sense Innovation, they are allowing those affected by Bell’s palsy to monitor their recovery, and send updates to specialists. By monitoring their progress remotely, therapists will be able to identify those Bell’s palsy patients who are not improving and thus reduce unnecessary travel, minimise the development of chronic facial disability and motivate adherence to the rehabilitation regime.


Development of a Generalized Modules for Membrane Antigens vaccine against gonorrhoea

There are 106 million cases of gonorrhoea each year that disproportionately affect women and new-born children, particularly in low-income countries. With increasing levels of anti-microbial resistance, there are growing concerns about untreatable gonorrhoea. There is a clear need for a vaccine against gonorrhoea, but none is available. 

Professor Cal MacLennan at the Jenner Institute, University of Oxford, wants to develop a Generalized Modules for Membrane Antigens (GMMA) vaccine candidate for gonorrhoea. It will exploit the ability of Gram-negative bacteria to shed outer membrane blebs displaying antigens including lipo-oligosaccharide and multiple membrane proteins which are targets of functional/bactericidal immune responses. GMMA are easy to manufacture and highly affordable. They are more immunogenic than equivalent subunit vaccines, having an adjuvant effect through delivery of signals to the innate immune system. 

The key goal of the project is to establish preclinical proof-of-concept for suitability of the GMMA approach for vaccine against gonorrhoea. The future potential healthcare benefits are a major global reduction in gonorrhoea, and improvement of reproductive and maternal/new-born health.

Immune-complex mimetics (ICMs): an adjuvant free approach to controlling the major diseases for which no vaccines are available

For many serious diseases, including malaria, there are currently no effective vaccines. Many vaccines under development also require co-administration with adjuvants that often have ill-defined mechanisms of action, are difficult to manufacture, are often unstable, and can have toxic side effects in humans.

Richard Pleass, from the Liverpool School of Tropical Medicine, has developed, patented, and licensed a platform technology that is able to cross-link immune receptors, found on antigen presenting cells, with high specificity and avidity. This Pathfinder Award will allow Richard and his team to determine if this technology can be repurposed for the delivery of antigens directly to dendritic cells for use in vaccines.

It is hoped that this approach will dispense with the need for adjuvants accompanying vaccines, by mimicking the natural immune-potentiating effects of immune-complexes. Although immune-complex mimetics may be suitable for any disease for which vaccines are required, the Award willl use model antigens from malaria to determine if this technology is feasible for vaccines. If this proof-of-principle Award works with the malaria model antigens, the technology should also work for any ligand for which multimerisation may endow useful therapeutic or diagnostic properties.

Development of an effective inactivated rotavirus vaccine (IRV) for developing countries: definition of rationale, business case, technical feasibility and overall development plan

This Pathfinder Award to Dr Audino Podda at the Novartis Vaccines Institute for Global Health in collaboration with Dr Jean-Pierre Amorij at InTraVacc in the Netherlands will provide pilot funding to assess the technical and commercial feasibility of developing a candidate inactivated rotavirus vaccine. The award will be used to assess if this candidate vaccine could provide advantages over existing live vaccines to offer a more effective and lower-cost solution for those most at risk of severe diarrhoea caused by rotavirus infection.


Development of an AAV vector for treatment of Batten disease caused by mutations in TPP1 (CLN2 disease)

CLN2 disease is the second most common subtype of the neurodegenerative disorders neuronal ceroid lipofuscinoses (NCL), or Batten disease. Children with the disorder have progressive visual failure, dementia, seizures and premature death. There is no curative or preventive therapy. The combined incidence for NCLs is at least one in 100,000, with more than 30% caused by mutations in the lysosomal enzyme tripeptidyl peptidase 1 (TPP1 or CLN2). About four to five new cases of CLN2 disease are diagnosed in the UK each year. There are likely to be at least 18 new cases in Europe each year and 360 worldwide.

This project seeks to develop ocular gene therapy for CLN2 disease. Other less common types of NCL, especially CLN1, CLN5, CLN10 and CLN13 diseases, should be responsive to the same proposed strategy and Dr Sara Mole, University College London, anticipates that the results will also facilitate the progression of these therapies to a wider clinical application for inherited retinal degeneration that is part of a syndromic retinal dystrophy.

Eye drop delivery of age-related macular degeneration drugs

This project will develop and test the efficacy of a peptide-based eye drop to deliver anti vascular endothelial growth factor (anti-VEGF) to the retina for treatment of neovascular age-related macular degeneration (AMD). Unlike current treatment regimens, which involve delivery of anti-VEGF by intraocular injections with associated complications, this peptide formulation will permit delivery of an established AMD treatment to the retina in an eye drop form. This drug delivery route provides a significant improvement for patients and will reduce clinic time and the stress of injections and remove some of the associated risks of the treatment. 

Dr Felicity de Cogan, University of Birmingham, will investigate the peptide’s ability to transport large molecules to the retina and will then evaluate the ability of the eye drop formulation to deliver equivalent therapeutic concentrations of anti-VEGF to those delivered by intraocular injections. This translational research project will provide part of the necessary preclinical data required for phase I clinical trial in humans. 

Strengthening the neuromuscular junction as a new concept for the treatment of congenital myasthenic syndromes and motor neuropathies with synaptic dysfunction

Disruption of the development and maintenance of the neuromuscular junction (NMJ) through mutations in the genes encoding its components or auto-antibodies against its elements lead to congenital myasthenic syndromes (CMS) and acquired myasthenia gravis (MG) respectively. These disorders result in impaired neurotransmission and fatigable muscle weakness. The phenotypical spectrum of NMJ dysfunction is expanding and several recently identified mutations in presynaptic NMJ proteins have been shown to cause hereditary motor neuropathies, and NMJ abnormalities have been demonstrated in genetic neuropathies. Current treatments for these conditions are limited and mainly symptomatic. Development and maintenance of the NMJ critically depends on the agrin/LRP4/MuSK pathway, whereby an active neuronal form of agrin is secreted by the nerve terminal which binds to its receptor LRP4 on the muscle fibre surface. The naturally occurring form of agrin is highly insoluble, and its activity is counteracted by cleavage by a specific serine protease (neurotrypsin). 

Neurotune, a Swiss biotech company, has developed a modified form of agrin (NT-1654) which is soluble and resistant to specific proteolysis. We propose to test NT-1654 in mouse models of human CMS (mice with mutations in the AGRN and the DOK7 genes) and in a mouse model of hereditary motor neuropathy (GARS). 

The key goals of the projects are: to provide evidence that NT-1654 improves neuromuscular transmission in these mouse models, as measured by functional muscle performance, life span, electrophysiological and morphological analysis of the NMJ phenotype and to identify the pharmacokinetic properties and molecular mechanisms of improved neuromuscular transmission with NT-1654 through analysis of its effects in nerve-muscle co-cultures, providing further evidence for its use as a therapeutic reagent in clinical trials. We will also identify safe, non-toxic doses in the mouse models being tested through preliminary dose finding studies. If our initial experiments provide evidence that NT-1654 is safe and effective in these mouse models, we will apply for a further grant to test NT-1654 in an early-phase clinical trial in a small cohort of patients with DOK7-related CMS. In the longer term we anticipate that NT-1654 will improve treatment options and quality of life for the spectrum of patients with NMJ dysfunction.

Engineered Treg Therapy for Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating condition of the central nervous system. Although several disease-modifying treatments (DMTs) have been approved to reduce the frequency of clinical relapses, most patients continue to clinically deteriorate under current therapy schedules. Autologous haematopoietic stem cell transplantation can have lasting beneficial effects for patients, but the procedure requires aggressive myelo-ablative conditioning which is associated with substantial toxicity. Neither DMTs nor stem cell transplantation can mediate antigen-specific suppression of the immunopathology of MS. Regulatory T cells (Treg) have the ability to suppress unwanted immune responses of T cells, 8 cells and inflammatory myeloid cells and we have previously shown in a murine model that T cell receptor (TCR) gene transfer is a robust technology to generate antigen-specific Treg. 

Professor Hans Stauss, University College London, will use cell engineering technologies to produce Treg that specifically suppress inflammation in the central nervous system. The planned preclinical work is expected to provide the basis for clinical trials in patients with MS. 

Hit discovery for schistosomiasis

At least 240 million people have schistosomiasis, a neglected infectious disease caused by parasitic worms.  With no vaccine near clinical deployment, schistosomiasis control depends on one chemotherapeutic agent, praziquantel (PZQ). This has a relatively low clinical cure rate and is ineffective against juvenile worms, which means repeat treatments are often necessary. Based on the agent’s low efficacy and its increased use in mass drug administration programmes, driving resistance is a major concern.

Professor Karl Hoffman will use Aberystwyth University’s automated, high-throughput screening platform, Roboworm, to screen a unique set of novel chemotypes for anti-schistosomal activity. The aim is to identify starting points for a drug discovery programme. 

In collaboration with the Dundee Drug Discovery Unit, the new anti-schistosomal hits will be used as part of a PZQ replacement or combinatorial strategy to treat people in schistosomiasis-endemic regions.

Production of a bivalent monoclonal antibody as a potent new immunotherapy for pancreatic cancer

Pancreatic cancer is the twelfth most common cancer in the world and is often fatal. Immunotherapy, which involves stimulating patients’ immune responses, has shown great promise in recognising and killing other types of cancer. This makes identifying new targets and therapeutic approaches for pancreatic cancer very important. 

Many different sugars are attached to proteins and lipids to enhance their function.  In cancer, these sugars are significantly altered, making them specific targets for immunotherapy. Professor Lindy Durrant and her team at the University of Nottingham have developed monoclonal antibodies (mAbs: protein drugs) that specifically target the sugars expressed on pancreatic cancers. These mAbs can kill cancer cells and stimulate the patient’s own immune response to prevent the cancer from coming back. 

Sugars are excellent targets as they have high expression on cancers and low expression on a very limited number of normal tissues. However, the normal expression can still lead to side-effects. To reduce these, the project team will combine two mAbs, to allow them to target two different sugars that are expressed on cancers but not on normal cells. This could lead to a new therapy for pancreatic cancer.

Alternative therapies to prevent intoxication by snake bites

Snake bite accidents primarily affect rural communities and can lead to death or physical and psychological disability. As well as systemic organ failure, extensive local necrosis at the site of a snake bite often results in amputation and disfigurement, and there are long-term consequences such as chronic ulcers.

Currently, therapy involves an injection of anti-venom antibodies raised in horses to clear the venom toxins. But if the injection isn’t administered shortly after the snake bite, its effectiveness is very limited, and it doesn’t prevent local necrosis. 

Dr Vania Braga and her team at Imperial College London propose to perform a screen to identify drugs that can help to reduce the toxicity of the venom components. The toxic effects of the venom derail the function of different cells, killing or severely impairing their function. By helping cells to minimise the action of the venom, the toxins will be cleared from the body without major damage to the different organs and with reduced risk of local necrosis.

Assessing hybridisation to improve activity of antibacterial compounds

This project aims to develop potent inhibitors of bacterial peptidoglycan glycosyltransferase (PGT) enzymes. These antibacterial compounds could have huge potential as novel broad-spectrum systemic drugs targeting Gram-negative MDR ESKAPE pathogens, because they have a very low propensity for generating resistance. 

Dr Alastair Parkes and his colleagues at Evotec (UK) Ltd have already identified PGT inhibitors that demonstrate activity against Gram-positive pathogens, but absolute potency and Gram-negative activity need to be improved. 

The team will apply novel strategies for hybridisation with bacterial cell penetrant compounds to deliver highly potent PGT inhibitors with broad-spectrum activity.

Repurposing AMPAkines for enhancing myelin regeneration in multiple sclerosis

Multiple sclerosis (MS) affects around 2.5 million people worldwide, but none of the treatments currently available are fully effective. 

Myelin regeneration can occur spontaneously in demyelinating diseases such as MS and it is essential for functional recovery. However, the regeneration often fails, leading to sustained clinical disability. Promoting myelin regeneration is therefore an important therapeutic aim. 

Dr Ragnhildur Káradóttir and colleagues at the University of Cambridge have revealed a regulatory mechanism that controls the brain’s ability to repair itself. The team identified novel communication between stem cells, which are capable of repairing myelin damage, and nerve fibres that have lost myelin, which occurs in MS. When a drug that increases the ‘sensitivity’ of the stem cells to the electrical signals from nerve fibres is delivered, the capability of the stem cells to repair myelin damage is enhanced. The aim of the project is to provide clear proof of concept that the use of such drugs promotes myelin regeneration in MS. 

Identifying a pharmacological agent that is effective in enhancing myelin regeneration could potentially revolutionise treatments for other white matter diseases, in addition to MS. 

Topical soft-drug smoothened inhibitors: reducing surgical burden for Gorlin syndrome patients

Gorlin syndrome is a rare genetic disease. It affects around 2,000 people in the UK and one in 30,000 people worldwide.  

Gorlin syndrome patients are highly prone to the development of a form of skin cancer called basal cell carcinoma (BCC) and develop hundreds or thousands of cancers in their lifetime. BCC's are unusual cancers because they grow slowly and rarely spread to remote parts of the body. Although this makes surgery highly effective, patients need to undergo new surgeries every few months, causing pain and a build-up of disfiguring scars. This disfigurement is a cause of considerable stress and concern to Gorlin syndrome patients. Current oral treatments clear BCC tumours, but have severe side effects. 

Dr Christopher Woodland at the University of Dundee aims to develop a safe topical drug to treat BCC’s. The project team will modify existing drugs to incorporate specific chemical features (soft-drug) so that the drugs are rapidly eliminated by the body after exerting their local therapeutic effect in the skin. These new drugs will avoid the current side effects and provide a best-in-class treatment for Gorlin syndrome, transforming care by providing a safe alternative to surgery.

Using antibiotic resistance as an opportunity to tackle bad bugs

The emergence of bacteria that can resist antibiotics is a major health emergency. Many advances in medicine, including organ transplantation, increased survival of pre-term infants, cancer chemotherapy and surgery are dependent on antibiotics that prevent or treat infection. 

Antibiotics work by targeting processes that bacteria use but humans cells do not. For example, penicillin stops bacteria making cell walls, which human cells do not have. This means that penicillin can attack bacterial cells but not human cells. Unfortunately, when bacteria become resistant these bacterial processes can no longer be targeted.

The aim of this project is to use antibiotic resistance itself as a target for a new type of antibiotic. One of the most important types of resistance involves a bacterial enzyme that cuts up penicillin and similar antibiotics, and stops them from working. Dr Andrew Edwards and colleagues from Imperial College London will design new antibiotics that look similar to penicillin. However, when the enzyme cuts these antibiotics they will become lethal to the bacteria. In addition to killing resistant bacteria, the project team believe that this approach will also reduce damage to the good bacteria in the body, which are often harmed by conventional antibiotics.

Directed bone marrow homing as a strategy to embed T cells

T-cell therapies are quickly emerging as highly promising candidates for the treatment of infection, cancer and autoimmune disease. Critical for the success of these therapies is the need for T cells to engraft efficiently and then persist long-term. Current clinical protocols have employed ‘conditioning’ with chemo- or radiotherapy, with or without exogenous cytokines, to aid engraftment and survival of transferred cells. But these approaches are associated with significant risks to already sick patients and only have variable success in ensuring the persistence of adoptively transferred T cells. There is an important unmet medical need to develop safer and more effective ‘one-shot’ strategies to promote both the initial engraftment and survival of therapeutic T cells in patients.

Professor Ronjon Chakraverty has identified a completely novel strategy to overcome these hurdles. It involves overexpressing using the chemokine receptor CXCR4 to direct the T cells to the bone marrow, where they receive specific niche signals that promote engraftment and survival. Across multiple clinical applications, this strategy is designed to achieve a lasting therapeutic effect with a single dose of T cells.

A novel gamma delta T cell platform technology to enable drug-tunable targeting of CAR tumour-associated antigen targets

Cancer immunotherapy has been hailed as a potential turning point in the fight against cancer. But the current clinical reality is that cancer is still a global health problem, with some cancers being especially difficult to treat. 

Checkpoint blockade strategies that unleash latent T-cell responses against mutated neoepitopes by suppressing inhibitory pathways have produced potent and durable clinical responses in various settings. But approaches like this appear less effective in tumours with low mutational burden. 

Chimeric antigen receptor (CAR)-engineered T-cell-based approaches appear well placed to offer an alternative strategy. They have produced dramatic results in B-cell malignancies. But CAR trials also highlight the potential for lethal on-target-off-tumour toxicity. This is a major concern, as most proposed CAR targets are expressed at low levels in normal tissues. Circumventing this problem, particularly in the context of solid tumours, is arguably the greatest challenge in the CAR field. 

Professor Ben Willcox proposes a novel technology to address this, which will enable drug-tunable CAR T-cell recognition. His strategy exploits human Vγ9Vδ2 T-cells. These cells display MHC-unrestricted recognition of diverse cancer cell targets. And, uniquely, they are drug-controllable, exhibiting TCR-dependent cytolysis of target cells exposed to clinically-approved bisphosphonate drugs. Ben aims to provide a proof-of-principle for this strategy. The future potential is substantial, as it represents a platform technology that could be applied to multiple CAR targets and tumour settings.

Strengthening the neuromuscular junction as a new concept for the treatment of congenital myasthenic syndromes and motor neuropathies with synaptic dysfunction

Disruption of the development and maintenance of the neuromuscular junction (NMJ) through mutations in the genes encoding its components or auto-antibodies against its elements lead to congenital myasthenic syndromes (CMS) and acquired myasthenia gravis (MG) respectively. These disorders result in impaired neurotransmission, and fatigable muscle weakness. The phenotypical spectrum of NMJ dysfunction is expanding; several recently identified mutations in presynaptic NMJ proteins have been shown to cause hereditary motor neuropathies, and NMJ abnormalities have been demonstrated in genetic neuropathies. Current treatments for these conditions are limited in that they are mainly symptomatic and limited by systemic side-effects.

Development and maintenance of the NMJ critically depends on the neuronal factor agrin, and the agrin/LRP4/MuSK pathway. The naturally occurring form of agrin is highly insoluble and its activity is counteracted by cleavage by a specific serine protease (neurotrypsin). Neurotune AG, a Swiss biotech company, has developed a modified form of agrin (NT-1654) which is soluble and resistant to specific proteolysis. Through a Pathfinder Award, Professor Lochmüller and colleagues at Newcastle University will test the effect of NT-1654 in mouse models of human CMS and in a mouse model of hereditary motor neuropathy. The team aim to provide evidence that NT-1654 improves neuromuscular transmission in these mouse models and to identify the pharmacokinetic properties and molecular mechanisms of this improvement, thus providing further evidence for its use as a therapeutic reagent in clinical trials.

Development of novel polysialyltransferase inhibitors for the treatment of neuroblastoma

Neuroblastoma is the most common extra-cranial paediatric cancer, typically affecting children below 2 years of age. Up to 2,500 new cases are diagnosed in Europe and the USA combined each year. Despite recent advances in therapy, post-treatment relapse is common, meaning there is a desperate need for novel therapies, with 5-year survival for children diagnosed with high-risk disease currently less than 50%. The burden of drug-related toxicity experienced by these patients is such that the scope for further toxic chemotherapy is limited.

One strategy is to prevent disease progression by targeting processes that drive metastatic spread of the cancer. Dr Robert Falconer and colleagues at the Institute of Cancer Therapeutics, University of Bradford are developing a completely novel approach to therapy, by targeting polysialyltransferase (polyST), an enzyme which plays a key role in neuroblastoma dissemination. PolyST is responsible for the synthesis of polysialic acid, which is exclusively expressed on neuroendocrine tumours, providing an opportunity for a non-toxic, selective therapy for neuroblastoma.

This Pathfinder project will focus on validation of a series of hit polyST inhibitors using biophysical techniques, and to use this information to identify new inhibitors using computational chemistry and in vitro pharmacological assays. Beyond this Pathfinder award, this work will pave the way to lead identification and demonstration of pre-clinical proof-of-concept.

A new biomaterial platform for integrated cell therapy research, manufacturing and clinical administration

The development of cell therapeutics, and their clinical administration, is staged in an inefficient, compartmentalised manner. There are major disconnects along the development pathway (from the research phase right through to clinical administration), with cellular performance expected to be replicable across 2D and suspension formats and also within complex biological environments. Furthermore, there are specific additional barriers to commercial uptake, which include high cost, poorly-scalable manufacturing, reliance on damaging proteolytic enzymes for cell harvesting and poor cell retention and survival post-implantation.

Dr Robin Quirk and the team at Locate Therapeutics propose to address these challenges by exemplifying their Reversible Porous Matrix (RPMax) platform as an embedded constant across the entire cell therapy value chain. RPMax is a new, thermoreversibly-setting particle-based matrix for tissue repair, offering opportunities for stem cell research, fully-automatable 3D cell manufacturing and clinical administration. This project aims to tailor the platform to key clinical cell types, to demonstrate performance benefits over current approaches and generate preclinical proof-of-concept data.

A novel gene therapy construct providing neuro-protection against glaucoma

Glaucoma is the second leading cause of blindness worldwide. The NHS estimates that there are more than 500,000 people diagnosed with glaucoma, with many more unaware that they have the condition. In 2010, it was estimated that 8.4 million people worldwide were blind from primary open-angle glaucoma which is predicted to rise to over 11 million by 2020.

Elevated ocular pressure is associated with glaucoma and is the focus of current treatments. However, high pressure is only a risk factor, and not the sole cause of the disease, with 10% of glaucoma sufferers having normal pressure. This, combined with poor treatment compliance leads to the blindness of glaucoma sufferers. While the cause of glaucoma is multi-factorial, the disease ultimately leads to death of retinal ganglion cells, which causes blindness.

Dr Peter Widdowson and the team at Quethera are utilising recombinant adeno-associated viral vector-based gene therapy to deliver neuro-protectants, shielding retinal ganglion cells, preserving them from death, and ultimately delaying blindness associated with the disease following a single injection to the eye. The Pathfinder Award will allow individual components of the gene therapy to be examined in vivo and ensure that they are functioning at optimal levels before they are assembled into the final gene therapy construct.

Identification of small molecule Onchocerca macrofilaricidal leads for the treatment of river blindness

Professor Fidelis Cho-Ngwa at the University of Buea, Cameroon, in collaboration with industry partner Merck, will use this Pathfinder Award to initiate a drug discovery project to develop a cure for onchocerciasis. Onchocerciasis, also known as river blindness is a neglected tropical disease, afflicting some 37 million people in poor tropical countries.

Despite being the second leading infectious cause of blindness globally, and a significant contributor to low life expectancy in the endemic countries, there is yet to be a cure (a macrofilaricide) for the disease. A macrofilaricide, especially one that does not kill Loa loa, to avoid serious adverse events, is a critical unmet need. Being a neglected disease, a not-for-profit strategy, based on global donations and philanthropy would be required to develop the drug.

Merck has 2.5 million diverse small molecules in its portfolio. In response to a WIPO Re:Search request, Merck will donate highly potent molecules, most of them HSP90 inhibitors for testing in well-established phenotypic assays and jird model at the pan-African ANDI Centre of Excellence for Onchocerciasis Drug Research, University of Buea, Cameroon. Inhibition of HSP90, a target present in Onchocerca, has previously been shown to be potent against filariae. At the end of the Pathfinder project, the team hope to deliver a handful of macrofilaricidal leads to support global efforts for the development of an onchocerciasis cure, that can be used in control programmes to eliminate the disease, and also safely used in areas where L. loa is also prevalent.

Development of small molecule inhibitors of Ebola virus genome replication

This Pathfinder project will address infection with Ebola virus (EBOV), which has a human mortality rate of over 50%. EBOV is a member of the Filoviridae family (genus Ebolavirus), a negative strand RNA virus that is highly transmissible and causes severe haemorrhagic fever.

The recent outbreak of EBOV in West Africa has highlighted the lack of effective therapeutic options for the treatment of this infection. Efficacious small molecule inhibitors of the virus are therefore needed for the rapid treatment of EBOV infected individuals, but their development has been hampered by the requirement to propagate EBOV under Biological Safety Level 4 (BSL4) containment.

The project team, led by Professor Mark Harris at University of Leeds, propose to use a combination of in silico drug design and a mini-genome system, which accurately and faithfully recapitulates the essential processes of EBOV gene transcription and genome replication under BSL2 conditions. The team will design small molecule inhibitors based on known high-resolution structures of EBOV proteins involved in these processes, in particular focussing on the essential nucleocapsid protein. This approach builds on existing strengths at the University of Leeds, combining an innovative approach to in silico drug design with extensive experience in both virology and structural biology. The project aims to deliver drug-like lead compounds that can be further developed into therapeutic agents.

New therapeutic avenues in Sjogren’s syndrome: exploring the role of PEPITEM in an orphan disease

Sjogren’s syndrome is the second most diffuse rheumatic autoimmune disease in the UK. Current treatment includes eye drops and saliva substitutes. In some cases patients are treated with immunosuppressive drugs but with scarce benefit. There is no disease-modifying therapy for this disease and it is not a priority area of research for the pharmaceutical industry.

It is known that Sjogren’s syndrome is driven by the recruitment of immune cells into the salivary glands. The subsequent production of autoreactive antibodies destroy the salivary tissue and drive systemic manifestations such as arthritis and fatigue. To enter the salivary glands, immune cells first need to cross the blood vessel wall. Importantly, Dr Francesca Barone and colleagues at the University of Birmingham have identified a novel molecule called PEPITEM that stops the recruitment of immune cells.

With Pathfinder funding, Dr Barone and her team aim to determine whether PEPITEM levels can predict who will develop Sjogren’s syndrome and whether therapeutic administration of PEPITEM prevents salivary gland inflammation in models of the disease. By better understanding the biology of PEPITEM, it may be possible to address both diagnostic and therapeutic needs for these patients.

Development of novel antagonists of the cell surface adrenomedullin 2 receptor for the treatment of pancreatic cancer

The protozoan parasite Cryptosporidium causes acute enteritis with severe diarrhea as lead symptom. Recent large-scale epidemiological analysis of the causes of life-threating diarrhea in small children around the world has identified Cryptosporidium as the second most important diarrheal pathogen after rotavirus.

Importantly, in those patients in gravest danger, malnourished children and immuno-compromised patients, nitazoxanide shows no benefit over placebo. Drug screening so far has been limited, and the overall research and development infrastructure for this important pathogen is underpowered, in part this is the consequence of lack of suitable experimental tools.

This Pathfinder Award project will synergize the University of Georgia Research Institute’s (UGA) expertise in parasite molecular genetics with the Novartis Institute for Tropical Diseases (NITD) expertise on phenotypic screening and drug discovery. Taking advantage of the UGA team’s recent breakthrough with transgenesis, they will develop luciferase based screening assays in tissue culture and animal models and benchmark them against staining-based assays.

Transgenic assays are likely to have multiple advantages including higher sensitivity, homogenous read-out and exquisite specificity and they will enhance throughput in vitro and in vivo. The team will use these technologies to run a pilot phenotypic screen with a set of chemically diverse anti-parasitic compounds. The deliverables of the project are validating a reporter based phenotypic assay that will enable comprehensive cryptosporidiosis drug discovery. The project will expect to identify a set of in vitro and in vivo active compounds that will be used to explore target-deconvolution.

Novel wall teichoic acid inhibitor for treatment of bacterial infections

Effective treatment of bacterial infections is an essential component of modern medicine. To that end, antibiotics have played a central role in saving millions of lives. Antibiotic resistance – when bacteria change so that antibiotics no longer work - is growing at a dangerously high rate and poses one of the greatest public health threats of our time. Antibiotic resistance would threaten routine surgery as infections become untreatable. Some types of treatment such as cancer chemotherapy and organ transplantation, which suppresses the patient’s immune system, would no longer be viable.

There is a need for the development of new antibacterial compounds especially with novel modes of action. Dr Ajay Mistry and the team at Oppilotech Ltd. have discovered a compound (OPT-1) that has potent antibacterial properties and is modulating a novel pathway in bacteria that is not targeted by any of the approved antibiotics. In vitro data has also been generated that indicates that OPT-1, in some isolates of MRSA, reverses their resistance to β-lactams, making them sensitive to antibiotics to which they were once resistant. This “potentiating” observation could have an enormous positive impact to the antibiotic landscape by making once obsolete antibiotics useful again. The project is aimed at further characterising the antibacterial and re-sensitising activities of OPT-1.

Identification of novel compounds for the treatment of pulmonary hypertension

Pulmonary arterial hypertension is an incurable progressive condition and has a devastating impact on the ability to lead a normal life. The condition causes constriction of pulmonary arteries, characterized by high blood pressure in arteries of the lungs, ultimately leading to right ventricular heart failure and death.

In patients with heart failure, injection of the peptide apelin produces a beneficial vasodilation of the peripheral vessels and acts as a very potent positive inotrope to increase cardiac output by acting at a single G-protein coupled receptor. The peptide is down-regulated in pulmonary arterial hypertension and it is proposed that an apelin agonist is required to replace the missing endogenous peptide.

A limitation in the use of agonist drugs that mimic the action of endogenous chemical messenger, is that in addition to activating G-proteins to cause the desired therapeutic effect, signalling can involve coupling to β-arrestin, leading to unwanted internalization and desensitization, silencing the target receptor. A collaboration between Dr Anthony Davenport, Dr Janet Maguire Professor Robert Glen from University of Cambridge has led to the discovery of the first ‘biased’ peptide agonist at the apelin receptor, that preferentially stimulate G-protein pathways over β-arrestin recruitment, with reduced internalization and desensitization.

The first-in-human, proof of principle studies show the ‘biased’ agonist improved vasodilatation and inotropic actions without receptor desensitization. The apelin receptor is one of the first G-protein coupled receptors pathways tractable to the design of biased agonists with proof-of-concept for utility in the clinic. The aim of this award in collaboration with the University of Dundee Drug Discovery Unit is to identify small molecule biased apelin receptor agonists with drug like properties.

Discovery and preclinical development of pan-serotype small molecule inhibitors against dengue virus NS5 RNA-dependent RNA polymerase (RdRp) using fragment screening

Dengue is the most important mosquito-borne disease of humans and an important tropical infectious disease. The National Institute of Allergy and Infectious Diseases in the US lists the causative agent, dengue virus (DENV), which has four serotypes, as a 'category A' priority bio-threat pathogen. Approximately one third of the world’s population is at risk of infection, which occurs most frequently in children aged under 15.

The spread of DENV in sub-tropical and tropical regions of the world has occurred over just a few decades due to globalisation and a failure to control the primary vector Aedes aegyptii. Ae. Albopictus, a secondary DENV vector, is spreading to cooler climates and so the disease is spreading further. A recent 2014 outbreak in Portugal underlines this concern. There are currently no marketed treatments for DENV infection, so there is a real need for an effective and safe treatment.

The ultimate aim of Effecta Pharma's dengue drug discovery programme is to identify pan-serotype inhibitors of the DENV NS5 polymerase protein for the treatment of dengue fever, that bind to allosteric pockets of this critical viral protein, inhibiting viral replication and producing an antiviral effect. The Pathfinder Award will allow the development of the first step in this programme - the technology to target the NS5 conserved region and identify the first chemical starting points for drug discovery. Beyond the Pathfinder Award, these chemical starting points will be used for lead identification and optimisation, ultimately resulting in preclinical candidate drugs to be tested in a clinical PoC study.

Accelerating developing world access to medicines

Dr Mary Moran and colleagues at Policy Cures aim to identify scaleable new solutions that can improve access to innovative new medicines for the developing world. As developing country economies have grown, their interest in, and capacity to pay for, pharmaceuticals has increased; as have commercial initiatives aimed at accessing developing pharma markets.

This Pathfinder Award project aims to provide an up-to-date picture of the changing landscape of L&MIC access to commercial medicines, with a focus on identifying emerging market-based solutions and assessing their ability to provide sustainable, scaleable developing world access to commercial pharmaceuticals, including for the poor.

Effect of AP301, a synthetic peptide mimicking the lectin-like domain of TNFalpha, on PHA type 1b causing mutations in the amiloride-sensitive epithelial sodium channel (ENaC)

This Pathfinder Award addresses the orphan disease pseudohypoaldosteronism type 1b (PHA type 1b), a life-threatening condition in which the sodium ion channel, ENaC, found in kidneys, colon, lungs, salivary and sweat glands has either reduced or no functionality.Non-function of ENaC results in loss of sodium in the urine and faeces and severe salt imbalance in the body.

Characteristic features are low levels of sodium (hyponatremia) and high levels of potassium (hyperkalemia) in the blood. The disease usually presents in newborns who fail to thrive and suffer from severe dehydration; other symptoms are abnormal heartbeat or shock due to salt imbalance and recurrent lung infections due to accumulated fluid. The condition does not improve with age and patients require life-long salt supplements and special treatment to remove potassium.

AP301 is a small biological molecule known as a peptide, composed of 17 amino acids, which activates the normal form of ENaC. Aerosolised AP301 has recently been shown to reduce lung liquid levels in patients suffering from acute respiratory distress syndrome (ARDS). The team at APEPTICO GmbH, in collaboration with the University of Vienna, will test whether AP301 activates ENaC into which the genetic defect causing PHA type 1b has been artificially introduced. The bioactivity of AP301 will be compared to that of a scrambled peptide, with the same 17 amino acids as AP301 but in a different sequence order, used as a control. If AP301 activates this defective ENaC, then it could be used to treat lung ailments of PHA type 1b patients.

Fetal haemoglobin (HbF) induction as a strategy to improve life quality in thalassemia: characterisation of HbF inducing products and preclinical models to predict therapeutic response

Beta-thalassemia treatment can still be considered a major unmet medical need, indeed thalassemia is a disease without an adequate treatment. Survival is increased, even in patients needing transfusions, in comparison with few years ago in most countries, but the quality of life is still poor for many patients and the complication of frequent transfusions is a major problem.

The concept of improved quality of life and possibly increased survival through increased fetal haemoglobin found widespread acceptance, but rather limited practical application for the lack of adequate drugs and lack of methods able to select the most appropriate patients. A team from Rare Partners and the Department of Life Sciences and Biotechnology at Ferrera University, Italy aim to advance their knowledge and transfer preclinical findings to clinical application in a relatively short time. Among the different drugs useful for management of thalassemia, the project team will focus their attention on those expected to be tested in clinical trials.

Use of secretion inhibitors as novel antifungal drugs

Meningitis due to the fungal pathogen Cryptococcus neoformans is rampant in Africa. Nearly one third of meningitis patients have shown treatment failure or resistance to currently available antifungals, demonstrating a tremendous need for the identification and development of new drugs to combat this fungal infection.

A Pathfinder Award to Prof. Marcio L. Rodrigues (Centre for Technological Development in Health, Fiocruz, Brazil), in partnership with the Institute of Pharmaceutical Technology of Farmanguinhos will provide pilot funding for the search of antifungals with the ability to inhibit the cellular traffic of key virulence factors used by C. neoformans to cause damage to host cells.

Development of new leads for animal trypanosomiasis

This programme builds on a DFID funded drug discovery and development collaboration between the University of Dundee’s Drug Discovery Unit and the Global Alliance for Livestock Veterinary Medicines (GALVmed) to continue medicinal chemistry optimisation and development of a novel lead compound series as a veterinary drug for the treatment of Animal African Trypanosomiasis in cattle.

The aim is to deliver a new treatment for this parasitic disease which is spread predominantly by tsetse flies in sub-Saharan Africa. It causes serious economic losses in in important livestock including cattle, goats and camels as a result of reduced productivity from clinical disease with severe anaemia, emaciation and mortality. Of particular importance is the reduction in draught power or traction of infected animals which leads to a corresponding reduction in the ability to prepare (plough) fertile land for production of important crops.

In the >10 million km2 of fertile land across 40 African countries infested with tsetse flies, which are inhabited by >56 million cattle and >70 million small ruminants, more than 3 million cattle die annually of the disease. This is despite the use of more than 150 million annual doses of existing commercially available animal drug treatments (trypanocides).These currently used trypanocides (including diminazene and isometamidium) were discovered more than 50 years ago and have limitations with respect to toxicity, safety and increased emergence of drug resistance.

No vaccines against the disease are available nor likely to be developed in the near future due to immune evasion via antigenic variation with trypanosomes. There is therefore a clear and urgent need for novel pharmaceutical livestock products for the treatment and prophylaxis of Animal African Trypanosomiasis.

Better drugs for cryptosporidiosis: hit-to-lead studies for confirmed MMV screening

Cryptosporidium parasites are intracellular and related to malaria parasites, but the infection is restricted to the intestinal epithelium.

This award is to fund the collaboration between the University of Vermont and Medicines for Malaria Venture (MMV) to determine if assets from the MMV Malaria Box have the pharmacologic characteristics required for a potential effective anti Cryptosporidium drug that differs from those needed to treat systemic infections.

Development of human induced pluripotent stem cells (iPSCs) in patients with neurodegeneration with brain iron accumulation (NBIA)

A Pathfinder Award to Dr Michael Hutton at Eli Lilly, in partnership with Professor John Hardy at UCL, will provide pilot funding for this Industry-Academic partnership to work on the rare disorders termed Neurodegeneration with brain iron accumulation (NBIA).

This is a group of rare, severe neurological disorders that are characterised by parkinsonism, cognitive decline and dystonia. The Award will fund the development of human induced pluripotent stem cells (iPSCs), which offers a way to develop in vitro models of these diseases in the laboratory, without exact knowledge of the disease mechanism(s). The cell characteristics will enable these models to be amenable to drug treatment from the array of therapeutic compounds held by Lilly going forward.

Developing a transformative therapy for inherited homocystinuria by correcting the misfolding of cystathionine beta synthase disease alleles

This Pathfinder Award brings together world-class researchers from Pfizer Inc.’s Rare Disease Research Unit in Cambridge, MA (US), including Dr Christine Bulawa of Pfizer, and the Structural Genomics Consortium (SGC) in Oxford (UK), including Dr Wyatt Yue, to study cystathionine beta synthase (CBS) deficiency. CBS deficiency is a rare genetic disorder in which affected people cannot process the amino acid methionine.

In many patients, a genetic defect causes the CBS enzyme to lose its optimal three-dimensional shape and prevents the enzyme from functioning properly. This leads to the build up of homocysteine in the body, causing an array of symptoms including early cardiovascular disease. The current standard of care is to reduce homocysteine levels by a methionine-restricted diet or supplementation with vitamin B6, a cofactor for the CBS enzyme.

However, this does not treat the underlying cause of the disease, and many patients do not respond to these treatments. During the course of this collaborative research, scientists at Pfizer and SGC aim to develop biochemical and molecular tools to facilitate discovery of a potential drug that restores the optimal shape and function to the defective CBS protein, thereby treating the root cause of the disease.

A preclinical feasibility study using recombinant homogentisic acid dehydrogenase as an enzyme replacement therapy for alkaptonuria

There are over 6000 known rare diseases and most are of genetic origin. One such condition is alkaptonuria (AKU), which is caused by a faulty enzyme. This means patients produce a chemical called homogentisic acid (HGA). Some HGA leaves the body in urine. The rest builds up in body tissues, eventually causing serious health problems.

Some of this HGA is converted into a black pigment. Over time this black pigment stains joint tissues, including bone and cartilage, causing early onset, severe arthritis. This is why AKU is also known as ‘black bone disease’. Patients also suffer severe pain and heart disease. Most AKU patients become severely disabled as life progresses and many of them end up wheelchair-bound.

There is no known cure for AKU and current treatment relies on pain management and joint replacement. This project's key objective is to test the idea of enzyme replacement therapy (ERT). We will make human enzyme in bacteria (as a method of manufacture) and then test it in mice with AKU. If this reduces the effects of AKU in the mice, then it might be possible to treat this debilitating disease for the first time. This is a collaboration between Protein Technologies Ltd and the University of Liverpool.

Enabling technology

Impact of somatic mutations in patients with myelodysplastic syndrome (MDS) receiving an allogeneic hematopoietic stem cell transplant (HSCT)

People with myelodysplastic syndrome (MDS) have myeloid haematological malignancies characterised by dysplasia, ineffective haematopoiesis and a high risk of progression to acute myeloid leukaemia. The International Prognostic Scoring System (IPSS), based on blood cell counts, marrow blast percentage and cytogenetics categorises patients into four prognostic groups: low, intermediate-1, intermediate-2 or high risk. Allogeneic hematopoietic stem cell transplant (allo SCT) remains the only potential curative treatment for MDS, but only patients with intermediate 2 or high IPSS are usually candidates for transplant due to transplant-related mortality which can affect 15-30% of cases. Next generation sequencing techniques of MDS genomes have identified mutations in genes implicated in RNA splicing, DNA methylation, chromatin regulation and cell signalling in about three quarters of patients. Some mutations are associated with distinct clinical phenotypes and many of them are associated with poor prognosis. However, most prognostic analyses have been performed independently of treatment, or in cohorts mainly treated symptomatically. 

Professor Ghulam Kufti at King’s College London will determine the prognostic impact of the molecular profile on post-transplant outcome by studying patients before and after the procedure.

Enabling novel penicillin-binding protein high throughput screens

Antibiotic resistance is a recognised global problem, with profound health and macroeconomic consequences, especially in emerging economies. Penicillin has been an excellent antibiotic, not least because it targets multiple penicillin-binding proteins (PBPs) simultaneously within a bacterium. Resistance has developed in most circumstances due to the acquisition of beta lactamases, efflux pumps or changes in outer membrane permeability. In only a few organisms, notably Streptococcus pneumoniae and Staphylococcus aureus, has resistance arisen by target alteration.

Professor Chris Dowson at the University of Warwick, in collaboration with AstraZeneca, will be revisiting the well-validated target of PBPs with new insight and screening capability. The goal is to develop novel laboratory assays for PBPs to find alternatives to penicillin that would sidestep current resistance mechanisms and address this problem. Professor Dowson and his team plan to screen 100,000 compounds initially, followed by hit characterisation and prioritisation for further development. The future plan is to run a full compound collection screen and progress promising hits to lead compounds.  

Vaccine microencapsulation for single dose delayed release delivery

Dr Anita Milicic at Oxford University has recently received Pathfinder Award funding to study alternative delivery methods for multiple-dose vaccines. The project aims to develop a new technology for vaccine delivery that would allow multiple (prime-boost) immunisations to be combined into a single-dose vaccine while retaining full efficacy.

The boost dose(s) would be encapsulated into polymer microcapsules, for a delayed delivery at predetermined time intervals within the body, and administered together with the priming vaccine thus mimicking the conventional prime-boost immunisation. This innovative technology could allow patients to achieve protection from a disease after just a single dose thus minimising sub-optimal vaccine coverage of the population.

Thinkthru: Using wearable technology to improve outcomes of psychological therapy for paranoia in psychosis

Paranoid thoughts (or worries about others intending to cause harm) affect approximately one in five of the general population, and are one of the most common symptoms of schizophrenia-spectrum disorders.

Talking therapies for paranoia have a promising but modest impact and need to be improved. People often struggle to remember or apply the skills learnt in therapy during their daily lives, and these memory and motivation problems mean that they tend to find therapy less useful.

This project will explore how digital technology can improve the effects of an intervention that has already been shown to be effective in helping people manage paranoia. Dr Amy Hardy and colleagues (Institute of Psychiatry, Psychology & Neuroscience, King’s College London), in partnership with the Helen Hamlym Centre for Design, Royal College of Art, will examine the potential of wearable technology to detect when people feel stressed, with the aim of triggering a mobile application to support the use of coping strategies when they are most needed.

Development of a biomarker to predict the need for biologic therapy at the time of Rheumatoid Arthritis Diagnosis

Of the 400,000 patients with Rheumatoid Arthritis in the UK, only 10% become eligible for a disease-modifying biologic therapy after delays of a year or more. About a third of these patients remain refractory for such therapy following their diagnosis. Delaying effective therapy reduces the chances of a patient ever achieving clinical remission and increases their risk of long-term joint damage.

Dr Mohini Gray and colleagues at the University of Edinburgh have discovered a predictive biomarker that can identify these patients at diagnosis, allowing for the rapid transition to effective biologic therapy. Utilising Next Generation Sequencing (NGS), of peripheral blood B cells, Dr Gray and her team will develop this predictive biomarker, to rapidly identify refractory patients. With Pathfinder funding the team will validate the assay using larger independent cohorts of patients. In addition, the assay will be simplified to test applicability to a real-life clinical setting.

Cloud based speech intelligibility platform for the hearing impaired

The World Health Organisation predicts that by 2020 the onset of adult hearing loss will be one of the top ten disease burdens facing modern society. The personal, mental and economic impact hearing loss has on the daily quality of life of those involved is significant and deeply personal.

The explosive growth of modern communications has exacerbated this problem due to poor voice quality and speech clarity over the telecoms network resulting in elements of stress, fear, embarrassment, anger etc. when trying to communicate with family, friends and colleagues over the phone. This Pathfinder Award project by Dr Matthew Turner from Goshawk Communications looks to ameliorate these problems by offering a unique software solution over a m-health platform within a telecoms/IP network.

It plans to test for hearing loss or needs - map the test results - and use the results to process an incoming voice call to enhance those frequencies that individual struggles to hear. This is performed on a real time, continuous basis to deliver a personalised voice signal based on that person’s specific hearing loss live over the telecoms/IP network that seeks to improve speech clarity and call quality tailored to their communication needs. It is a technology agnostic platform, independent of brand and manufacture bias making it globally accessible and scaleable in a capital, efficient way over existing carrier networks.

Nanoparticles for safe and efficient delivery of radionuclides for cancer diagnosis and therapy

Professor Clive Roberts and his collaborators in the medical school of the University of Nottingham aim to address the healthcare need to effectively and safely deliver radionuclides to tumours. This Pathfinder Award will further develop a nanoscale delivery platform based on FDA-approved materials that has the potential to seal radionuclides stably inside so as to minimise side effects during cancer therapy.

By utilising the clinically-proven enhanced permeation and retention effect (EPR effect) characterised by nanoparticles (<100nm) our prototype product has the potential to significantly improve the delivery efficiency of radionuclides compared to radionuclide-molecule conjugates. This improved efficiency will allow much lower amounts of radionuclides to be used, reducing risks for both patients and healthcare workers.

Independent Rare Disease Registry (IRDR) in Australia

The Murdoch University, Rare Voices Australia Ltd and Shire Australia Pty have been awarded funding to develop an Independent Rare Disease Registry. Its first deployment will be to develop a registry for Gaucher patients.

In Australia, a geographically diverse country with a fragmented health care system, all treated patients’ information is kept in manual annotated spreadsheets. As such, new highly relevant phenotypic measurements are not captured nor are they accessible for sophisticated data mining and integration with other registries and genetic repositories. This means that the Gaucher patient community is at a disadvantage relative to their international peers.

The GR will be developed as a first registry to ensure that relevant data collected will enable knowledge transfer of clinical and genetic information. This data will be utilised for the development of specific new compounds for rare diseases, including for Gaucher disease. In addition, the GR-IRDR will enable pharmaceutical companies, through an appropriate governance structure, to select suitable patients for clinical trials and allow for trial designs that address the increasing needs of both regulatory and reimbursement bodies for both existing treatments and for those which are still in the research and development phase.


Development of micro-computed tomography (μCT) for enhanced diagnosis and prognosis in interstitial lung diseases (ILD)

This project focuses on the diagnosis of long-term debilitating lung diseases, in particular idiopathic pulmonary fibrosis (IPF). It builds on pioneering work carried out by Professor Ian Sinclair at the University of Southampton in collaboration with the University Hospital Southampton. Traditionally, diagnosis is made using very thin sliced sections of lung that are examined under a microscope, looking for changes in the lung structure caused by disease. These sections provide only a very limited idea of how far disease has degraded the vitally important 3D structure of the lung

This work overcomes those limitations by using Nikon Metrology’s microfocus CT technology (designed and built in Tring, UK) to examine samples of human lung and produce a new diagnostic capability. The microfocus CT technology delivers digital scans with a resolution that is hundreds of times more detailed than conventional medical CT. Results will be validated against lung samples from patients who have a known diagnosis. Advanced digital analysis allows the airways, blood vessels and areas for gas exchange to be separately identified in 3D. 

This technique will ultimately enable the NHS to deliver earlier and more accurate diagnosis, improve patient outcomes and accurately target medication and surgery.

Metabolic stratification of luminal breast cancer for chemotherapy

Breast cancer is a common term describing several subtypes of the disease, each of which requires specific treatment. Previous research by Professor Gyorgy Szabadkai’s team has indicated that cancer subtypes diverge due to distinct adaptation mechanisms mediated by the mitochondrion, a subcellular organelle. 

This project will explore how mitochondria behave in different cancer types. It will also categorise cancers according to the genes which govern their behavior to inform their sensitivity to treatment . 

Professor Szabadkai and Dr Kevin Bryson at University of College London have devised a mathematical way to quantify mitochondrial gene expression (mGEP), which is the basis of the new classification. They will evaluate the metabolism of human tumours belonging to different genetic subtypes. This work will be done in collaboration with Professor Robert Stein and Dr Mariia Yuneva. 

Ultimately, this will help future efforts to develop a novel diagnostic tool to prevent overtreatment of the disease.

Retinoblastoma: screening for RB1 mutations by intra-ocular cell free DNA analysis

Retinoblastoma is the most common eye cancer in childhood and is almost always caused by mutations in the RB1 gene. These mutations can either be inherited or can develop just within the eye itself. 

Determining the nature of an individual’s mutation is crucial for patient care. The type of RB1 mutation can help to predict: whether retinoblastoma is likely to develop in the second eye; whether a child is at an increased risk of other types of cancer; and whether a child’s siblings are also likely to develop retinoblastoma.

Dr Stephanie Allen and her team at the Birmingham Women’s NHS Foundation Trust will analyse the DNA present in the eye fluid of children with retinoblastoma. They will then develop a screening test capable of detecting sporadic mutations in the RB1 gene that are only found in the tumour. Currently, this is only possible if an eye is removed. This is happening less because of the increase in successful chemotherapy and aggressive local therapy.  

A serum biomarker as a diagnostic for human and animal African trypanosomiasis

Trypanosomiasis is one of the most significant infectious disease threats in sub-Saharan Africa. It is caused by the trypanosome parasite, which infects humans and animals, and causes approximately 3 million deaths a year. At least 55 million cattle are at risk, with an annual cost of $2.5 billion in East Africa alone. Eradicating human trypanosomiasis by 2030 is a major target for the World Health Organization. 

Diagnosis of trypanosome infection is largely based on symptoms or insensitive microscopy . Large quantities of prophylactic drugs are used as a continuous measure to prevent disease. A few diagnostic options exist, but these rely on either antibodies to trypanosome antigens or amplification of DNA. Both have limitations: the antibody test cannot differentiate between active infection and exposure, and the DNA target often persists after successful treatment. 

This project, led by Dr Liam Morrison and Dr Finn Grey at the Roslin Institute, University of Edinburgh, aims to develop a serum biomarker as a diagnostic for human and animal trypanosomiasis. The project team has identified a biomarker in the blood of cattle infected with trypanosomes that can be used to develop an accurate and reliable diagnostic test. The team aims to further characterise this biomarker and, in collaboration with a partner company, develop cheap diagnostic tools that will allow rapid testing of cattle without the need for specialised equipment or training. 

Microcapillary serology: affordable and simple miniaturised multiplex ELISA to translate reference-lab infectious disease diagnostics into low-resource clinics

This project seeks to translate conventional high-resource diagnostic assays that are currently performed in clinical laboratories, into simple, low-cost microfluidic devices made from microcapillary film. Microcapillary film is a novel, mass-produced, microstructured material that is suitable for performing miniaturised biological assays, such as clinical diagnostic tests. 

Dr Alexander Edwards and colleagues at the University of Reading have already developed diagnostic test devices suitable for measuring cancer, inflammation and cardiovascular biomarkers, but the technology has not yet been tested for infectious disease diagnostics. Many emerging and existing infectious diseases present a high burden on low- and  middle- income countries, and so improved diagnostic tests must be affordable in this setting. Mosquito-borne viral infections such as dengue virus are a particular problem, although biomarkers of dengue virus infection have been extensively studied using conventional laboratory methods. Rapid tests are also available which are clinically useful but have limited performance. 

This project will assess the technical performance and clinical feasibility of microcapillary film devices for dengue virus diagnostics and surveillance in low- and middle- income countries, and compare microcapillary film devices with conventional laboratory and existing rapid tests.

MicroRNA diagnostics of filarial infection

Onchocerciasis, caused by infection with the filarial nematode Onchocerca volvulus, is responsible for 1.1 million years lived with disability. Over 15 million people are infected, of whom 99% are in Africa. More than 12 million people suffering from the infection have skin disease and 1 million are affected by vision loss. 

Extensive control programmes using ivermectin, aimed at eliminating the disease, have been successful in some regions. However, reports of sub-optimal responses to treatment may reflect emerging resistance. The most important immediate concern is the constraint on control programmes in communities co-infected with another filarial nematode, Loa loa, where ivermectin is contra-indicated because of the risk of severe adverse reactions associated with death of L.loa microflariae. 

A specific and sensitive point-of-care diagnostic test is urgently required for detection of onchocerciasis and loiasis. Dr Amy Buck and her collaborators aim to develop a diagnostic based on direct measurement of parasite-derived small RNAs in human urine or serum, which reports on the presence of live adult worms and can distinguish between species. Her approach aims to validate small RNA markers to distinguish between O.volvulus and L.loa infection, and test and optimise the most suitable purification or extraction method to be used in the field. An accurate diagnosis of infection status will allow direct monitoring of the efficacy of ivermectin and appropriateness of treatment in loiasis co-endemic communities. 

Wavelength modulated Raman spectroscopy for therapeutic drug monitoring

About 30-60% of the drugs that are administered don’t achieve clinical benefits for patients. This amounts to a waste of around £393 billion globally each year. It’s clear that one drug dose does not fit every patient. 

Therapeutic drug monitoring (TOM) is used for drugs that have a narrow therapeutic window with severe consequences, from toxicity through overdosing or not reaching therapeutic levels through underdosing. Currently, TOM analysis uses costly complex methods in which samples must be sent away to dedicated laboratories. With turnaround times of half a day, this is a period in which severe, potentially fatal, reactions to either overdosing or underdosing could occur.

M Squared Lasers will develop a Raman-based TOM analysis tool that is low cost enough to be widely available and that can be used repeatedly, at any time of day, quickly and easily. This will allow for drug concentrations to be monitored at the troughs of the dosing cycle several times a day. Importantly, the system will be portable and able to be operated by any non-specialist clinician. Such an instrument could drastically improve the current TOM clinical pathway, cancer survival rates and the therapeutic effects of drugs with narrow therapeutic windows.

Biomarkers discovery in the progressive bulbar palsy/amyotrophic lateral sclerosis clinical spectrum: combined tissue and fluid-phase proteomics

This Pathfinder Award aims to identify biomarkers that will support a stratified approach to the diagnosis, management and discovery of new therapeutic targets for progressive bulbar palsy, an aggressive form of amyotrophic lateral sclerosis with 5 year survival rates of 9-40%.

The award builds on a collaboration between Proteome Sciences Plc and Queen Mary’s School of Medicine and Dentistry. They are using a novel proteomics approach based around isobaric mass tagging which allows diseased tissue to be spiked into body fluids to identify proteins found in blood that are derived from and accurately reflect the disease process. These differentially expressed blood proteins will be useful as markers for early diagnosis and the monitoring of disease progression and may also help identify key disease pathways that can be targeted by new medicines.