Humans are rhythmic beings, with daily sleep/wake cycles affecting almost every aspect of physiology and behaviour. Our master circadian clock is known to reside in the suprachiasmatic nuclei (SCN) of the hypothalamus. Via multiple pathways, output from the SCN synchronizes peripheral oscillators throughout the body. The discovery of the molecular components of the core clock has provided new insight into the link between circadian biology and chronic diseases, but has not been exploited for drug discovery. With this work we will prepare chemical probes for the clock proteins REV-ERBalpha and RORalpha, characterise their activity in models of inflammation, and deliver lead optimised molecules for clinical development.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Systemic Lupus Erythematosus (SLE) is a chronic incurable disease caused by a person's immune system attacking organs and tissues such as the joints, skin, kidneys and brain. SLE affects one in 2000 individuals in the UK. Currently, treatment is selected based on a doctor's experience and on a 'trial and error' approach. Many agents take at least 6 months to show maximum improvement during which patients often require large steroid doses. It is recognised that long-term complications of lupus are associated with both ongoing 'grumbling' disease activity and chronic steroid use. Standard immunosuppressives such as mycophenolate mofetil (MMF) have had response rates of 50-60% in clinical trials and newer, more targeted' biological therapies such as rituximab, belimumab and epratuzumab also report response rates in trials of 40-60%. Clinical experience and a number of studies have however suggested that there are certain patients who respond very well to particular treatments. The goals of a stratified approach therefore would be to allow doctors to maximise major response rates whilst avoiding / minimising chronic steroid therapy and aligning therapy selection better with our understanding of the key disease process in an individual patient. Our consortium will identify and apply in the clinic, factors that predict excellent response to therapy to allow doctors to increase the early use of 'most effective' therapies. This 'stratified' approach will also improve the success of future trials of new treatments for lupus which to date has had a suboptimal record. To do this we will combine expertise from clinical and laboratory-based investigators, and link these with researchers working in the pharmaceutical industry. Our focus will be to identify factors that predict which patients do extremely well on any particular lupus treatment. We will start by focusing on a small number of drugs. As we demonstrate that this approach works well, we will be able to expand this method to other lupus treatments which are currently in development. We plan to re-analyse data already available from a number of large studies ongoing in the UK and internationally as well as to re-analyse data from previous lupus clinical trials. From these studies we will look for key predictive factors; such factors may include the type of lupus, genetic markers that the patient inherited and results of blood tests . In order to examine this question in even more detail, we plan to set up two parallel studies; one in patients with skin rashes due to lupus and one in patients with kidney involvement. In both these studies we will take biopsies to examine the affected tissue and also take blood and urine samples on a regular basis. These samples will be used to look in detail at how cells, proteins and other molecules change over time after a patient has been treated with a particular therapy. Combining this detailed information with the information gained from the larger studies we aim to better predict excellent levels of response to treatment. This information will be used to help develop devices and/or computer programmes for the clinic to help find the most appropriate and effective treatment choices for patients with lupus. We plan to test our results in a clinical trial to examine whether this approach actually has more benefit for patients. Running alongside this, we will study the economic costs of lupus to the health care system as well as the costs of lupus to the individual and society. We anticipate that treating the right patient with the right drug at the right time will help control lupus better in individual patients, improve their survival rates and reduce their needs for need for steroid treatment. We also anticipate that this approach will significantly improve the quality of life of patients with lupus whilst also providing financial saving for the healthcare and benefits system.

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania. The disease has many forms, ranging from localized and self-healing cutaneous leishmaniasis (CL) to the systemic visceral leishmaniasis (VL), which is fatal if not treated. There are more than 12 million people at risk of disease worldwide and an estimated 50 000 deaths per year due to VL. There are no vaccines and there are few drugs available. All the drugs have limitations, for example, resistance, long treatment courses, toxicity, methods of administration and high cost. In humans the Leishmania parasites survive and multiply inside macrophage cells, which in case of VL are found in the liver, spleen and bone marrow. For a drug to be effective it should ideally reach a concentration at the site of infection (it's pharmacokinetic property, PK) which can kill the parasite (it's pharmacodynamic property, PD) without being toxic to other parts of the body. The aim of a good dosing regimen is to deliver and keep effective drug levels at the site of infection to successfully kill all the parasites over several days. The aim of the chemists designing a new drug is to give it the properties that maximise its distribution to these sites of infection. The determination of the relationship between drug PKs and PDs is therefore important in both drug development and drug treatment. Currently we know very little about the PKs and PDs of any of the drugs used for leishmaniasis and nothing about drug action and drug concentration at the site of infection. The dosing regimens used in treatments today have not been optimised based upon this PK PD understanding, which could lead to improved efficacy, lower toxicity, and less chance of resistance; the same applies to the design of drug combinations. We aim to fill this knowledge gap by characterising the PK/PD relationships of established anti-leishmanial drugs and provision of predictive models that can be used in both drug development, by academic groups and the pharmaceutical industry, and in determining dose regimens and the best drug combinations. We will ensure that the successfully established methods and models are made available to the academic community and pharmaceutical and biotechnology companies with programmes in this field. We intend to make a contribution to the more cost-effective and efficient development of novel and much-needed therapeutic agents for this neglected tropical disease.

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.