Pseudomonas aeruginosa (Pseudomonas) is a bacteria which causes a wide variety of infections, including corneal (eye), lung and blood, resulting in significant disability and death worldwide. A recent surge in antibiotic-resistant Pseudomonas has prompted the World Health Organisation to advise new treatments must be developed as a 'high priority'. Recovery for many patients remains very poor even if their condition is treatable with antibiotics. For those with corneal (transparent window at the front the eye) infections, significant damage and scarring can lead to blindness. In Pseudomonas infections with poor outcomes it has been established that the bacteria inject a toxin, called Exotoxin U (ExoU), into human cells. ExoU rapidly kills the cells including immune cells sent to fight the infection. The bacteria evade the immune system to continue multiplying and causing damage. Inhibiting ExoU could provide a new treatment to reduce the severity, disability and death caused by this bacteria. We have identified 25 promising drugs which specifically inhibit ExoU. In test-tube models of corneal infections, the drugs reduce damage and show protective effects which help the cells heal. This occurs even at very low concentrations. Our data suggests they can be combined with antibiotics to improve these results. Significant research is required prior to human trials. This includes testing different concentrations, combinations, assessing how well they get to the site of infection, and testing them in clinically-relevant animal models. Protocols for administration are also required, including strength, frequency and length of the course. Demonstrating they work for infections in other organs, such as the lung, would prove they could be developed to treat and benefit more patients. My fellowship project will build on our initial work, with the following aims and objectives: 1) I will evaluate the ExoU inhibiting drugs in scratch and infection cell models, primarily in eye cells, but also lung cells to see if they will work in these too. Different concentrations and combinations will be tested, with and without antibiotics. Results will demonstrate their potential and help develop the treatment protocols. 2) I will measure the concentration of the ExoU inhibiting drugs that get to the site of infection. I will utilise a model which uses a donor human cornea attached to a glass artificial model of the anterior chamber of the eye (the front part which contains fluid). The drug, as an eye-drop, will be applied to the surface, and samples of the fluid within will be taken at different time-points. The concentration of drug in these samples will be measured. This is important information which will aid the development of the treatment protocols and advance the drugs towards human trials. 3) I will evaluate the ExoU inhibiting drugs in a more advanced infection model. Pig corneas (by-products of the food industry) will be infected with Pseudomonas and treated with the ExoU inhibitors using the protocols developed in objectives 1 and 2. This will help identify the most promising drugs and refine the treatment protocol which will be used in further experiments. Conducting this experiment will significantly reduce the number of animals required in subsequent experiments. 4) When I have identified the two best drugs and protocols, I will evaluate these further in a mouse model of corneal infection. This work will be conducted with my collaborators in the United States who have an ethically approved model and the expertise. These experiments will provide the necessary data, including the safety data, which we will require to proceed to human clinical trials. My project will significantly develop the knowledge required to progress these ExoU inhibiting drugs towards human trials. The ultimate aim is that the drugs will be used to treat patients with Pseudomonas infections to improve their recovery and overall outcome.

Vaccine manufacturing systems have undergone evolutionary optimisation over the last 60 years, with occasional disruptions due to new technology (e.g. mammalian cell cultures replacing egg-based systems for seasonal influenza vaccine manufacture). Global vaccination programmes have been a great success but the production and distribution systems from vaccines still suffer from costs associated with producing and purifying vaccines and the need to store them between 2 and 8 degrees C. This can be a challenge in the rural parts of low and middle income countries where 24 million children do not have access to appropriate vaccinations every year. An additional challenge is the need to rapidly respond to new threats, such as the Ebola and Zika viruses, that continue to emerge. The development of a "first responder" strategy for the latter means that there are two different types of challenges that future vaccine manufacturing systems will have to overcome: 1. How to design a flexible modular production system, that once a new threat is identified and sequenced, can switch into manufacturing mode and produce of the order of 10,000 doses in a matter of weeks as part of localised containment strategy? 2. How to improve and optimise existing manufacturing processes and change the way vaccines are manufactured, stabilised and stored so that costs are reduced, efficiencies increased and existing and new diseases prevented effectively? Our proposed programme has been developed with LMIC partners as an integrated approach that will bring quick wins to challenge 2 while building on new developments in life sciences, immunology and process systems to bring concepts addressing challenge 1 to fruition. Examples of strategies for challenge 1 are RNA vaccines. The significant advantage of synthetic RNA vaccines is the ability to rapidly manufacture many thousands of doses within a matter of weeks. This provides a viable business model not applicable to other technologies with much longer lag phases for production (viral vectors, mammalian cell culture), whereby procurement of the vaccine can be made on a needs basis avoiding the associated costs of stockpiling vaccines for rapid deployment, monitoring their on going stability and implementing a cycle of replacement of expired stock. In addition, low infrastructure and equipment costs make it feasible to establish manufacture in low-income settings, where all required equipment has potential to be run from a generator driven electrical supply in the event of power shortage. This fits the concept of a distributed, flexible platform technology, in that once a threat is identified, the specific genetic code can be provided to the manufacturing process and the doses of the specific vaccine can be produced without delay. Additional concepts that we will explore in this category include the rapid production of yeast and bacterially expressed particles that mimic membrane expressed components of pathogenic viruses and bacteria. Examples of strategies for challenge 2 build on our work on protein stabilisation which has been shown to preserve the function of delicate protein enzymes at temperatures over 100 degrees C. We shall exploit this knowledge to develop new vaccine stabilisation and formulation platforms. These can be used in two ways: (a) to support the last few miles of delivery from centralised cold chains to patients through reformulation and (b) for direct production of thermally stable forms, i.e. vaccines that retain their activity for months despite being not being refrigerated. We believe that the best way to deliver these step changes in capability and performance is through a team-based approach that applies deep integration in two dimensions: between UK and LMIC partners to ensure that all the LMIC considerations are "baked in" from the start and between different disciplines accounting for the different expertise that will be required to meet the challenges.

The Innovation and Knowledge Centre in Regenerative Therapies and Devices will provide a sustainable platform to address the creation of new technologies in Regenerative Therapies and Devices. It will promote their accelerated adoption, with increased reliability, within a complex global marketplace with increasing cost constraints. Therapies and devices which facilitate the regeneration of body tissues offer the potential to revolutionise healthcare and be a catalyst for economic growth, creating a new business sector within healthcare technology. The IKC RTD will build upon the culture and research landscape of the University and its partners (industry, NHS and intermediaries/users) through the development of new innovation infrastructure and practices which deliver major clinical, health and industry outcomes.In the first year of operation the IKC has:1. Recruited and established a core innovation team to manage and grow the activities of the IKC.2. Established academic supply chain, new centre with 160 researchers.3. Won 50m new research income, funding over 120 research projects.4. Defined a new strategic framework for innovation.5. Established an innovation pipeline with stage gates and criteria for progression.6. Defined and developed the IP portfolio through definition of the unique capabilities.7. Established a pipeline of 63 collaborative innovation projects.8. Engaged with 26 different companies in collaborative innovation projects.9. Established a wider network of 80 plus companies.10. Contributed to nine new products that have reached the market.11. Defined a model for sustainability of IKC RTD.12. Received significant national and global recognition through political visits and extensive media coverage for research and innovation.

The Centre for Doctoral Training in Tissue Engineering and Regenerative Medicine will provide postgraduate research and training for 75 students, who will be able to research, develop and deliver regenerative therapies and devices, which can repair or replace diseased tissues and restore normal tissue function. By using novel scaffolds in conjunction with the patient`s own (autologous) cells, effective acellular regenerative therapies for tissue repair can be developed at a lower cost, reduced time and reduced risk, compared to alternative and more complex cell therapy approaches. Acellular therapies have the additional advantage as being regulated as a class three medical device, which reduces the cost and time of development and clinical evaluation. Acellular technologies, whether they be synthetic or biological, are of considerable interest to industry as commercial medical products and for NHS Blood and Transplant as enhanced bioprocesses for human transplant tissues. There are an increasing number of small to medium size companies in this emerging sector and in addition larger medical technology companies see opportunities for enhancing their medical product range and address unmet clinical needs through the development of regenerative devices. The UK Life Sciences Industry Strategy and the UK Strategy for Regenerative Medicine have identified this an opportunity to support wealth and health, and the government has recently identified Regenerative Medicine as one of UK`s Great Technologies. In one recent example, we have already demonstrated that this emergent technology be translated successfully into regenerative interventions, through acellular human tissue scaffolds for heart valve repair and chronic wound treatment, and be commercialised as demonstrated by our University spin out Tissue Regenix who have developed acellular scaffold from animal tissue, which has been commercialised as a dCEL scaffold for blood vessel repair. The concept can potentially be applied to the repair of all functional tissues in the body. The government has recognised that innovation and translation of technology across "the innovation valley of death" (Commons Science and Technology Select Committee March 2013), is challenging and needs additional investment in innovation. In addition, we have identified with our partners in industry and Health Service, a gap in high level skills and capability of postgraduates in this area, who have appropriate multidisciplinary training to address the challenges in applied research, innovation, evaluation, manufacturing, and translation of regenerative therapies and devices. This emerging sector needs a new type of multidisciplinary engineer with research and training in applied physical sciences and life sciences, advanced engineering methods and techniques, supported by training in innovation, regulation, health economics and business, and with research experience in the field of regenerative therapies and devices. CDT TERM will create an enhanced multidisciplinary research training environment, by bringing together academics, industry and healthcare professionals in a unique research and innovation eco system, to train and develop the medical and biological engineers for the future, in the emerging field of regenerative therapies and devices. The CDT TERM will be supported by our existing multidisciplinary research and innovation activities and assets, which includes over 150 multidisciplinary postgraduate and postdoctoral researchers, external research funding in excess of £60M and new facilities and laboratories. With our partners in industry and the health service we will train and develop the next generation of medical and biological engineers, who will be at the frontier in the UK in innovation and translation of regenerative therapies and devices, driving economic growth and delivering benefits to health and patients

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