Towards a global research network for the molecular pathological stratification of leishmaniasis.

The leishmaniasis are parasitic diseases caused by one of several species of single cell parasites (Leishmania) that are transmitted to humans by the bite of infected phlebotamine sand flies. These diseases affect over 150 million people across 98 countries worldwide, including many low and middle income countries (LMICs). Some forms of leishmaniasis are fatal, whereas other are very stigmatising and affect quality of life, particularly in children and women. Few drugs are available for patients leishmaniasis and no vaccines are currently registered for use in preventing or treating these diseases. Importantly, the drugs that we do have are not universally effective and often have significant side effects. Sometimes patients even in the same geographical area will respond quite differently to therapy, and for some drugs effectiveness may vary widely between different countries. In order to make the best use of current and future drugs for the leishmaniasis, we need to understand more about why this is the case, and use that information to select appropriate drugs or drug combination for use in different settings. Using the appropriate treatment would save costs in health care, minimise the patient suffering that results from administering ineffective treatments, and reduce the economic burden of disease on patients, their families and communities.

In this proposal, we are aiming to lay the foundation blocks that will drive a new way of managing patients with leishmaniasis and conducting research into these diseases. We will use new molecular approaches to extract as much information as possible from small tissue samples that are collected from patients to diagnose their leishmaniasis, and use this information to start to develop new tests that can help clinicians decide on the best course of treatment. We will use the internet to ensure that the information obtained from these tissue samples is used most effectively for research, clinical decision making and for education and training. We will conduct an analysis of the added value of these changes in approach, in order to provide a case for their adoption by health systems in LMICs and by the funders of research. Ultimately, by adopting these practices we will seek to deliver improvements in health and economic prosperity in LMICs. The research we propose over the next two years will not provide all the answers, but will provide necessary proof of concept data to support applications for future funding that may allow us to realise this longer term ambition.

The leishmaniasis are complex diseases, showing great diversity in clinical presentation and in response to drug treatment, across individual patients as well as across geographic boundaries. The adoption of stratified approaches to treatment with existing as well as new drugs and /or drug combination therapies could have a considerable impact on the direct and indirect costs associated with treatment and significantly improve patient well-being. In this Foundation Award, we aim to set the scene for a change in the way we conduct clinical research in leishmaniasis. Using Nanostring nCounter analysis of formalin fixed paraffin embedded (FFPE) sections, we will maximise the data obtained from diagnostic tissue samples and use this information to start to develop multiplex point of care assays that can be used in a resource poor setting. We will assess the added value to research, clinical decision making and education and training that can be achieved thorough the development of an internet-based telepathology network, initially linking "scanning" hubs in Brazil and York with remote viewing stations in Sri Lanka and India. We will use a series of scoping workshops to i) inform the development of a new clinical grading tool for tegumentary leishmaniasis (based on advances being made for other dermatological diseases) and ii) to understand the health economic implications of adopting this approach and to seek evidence for added value for the research community and for health systems in LMICs. Each of the specific project aims has been structured to provide the necessary preliminary data and, where appropriate, explore the industrial partnerships necessary to underpin future funding applications and / or commercial sector engagement in 12-18mth time. At the completion of the Foundation Award, these studies will have also delivered new knowledge of importance in its own right and suitable for publication.

The leishmaniasis are global diseases with a particular impact on the health and well-being of populations in lower and middle income countries (LMICs). Tegumentary leishmaniasis, most often resulting in significant scaring, affects people in >40 LMICs and may lead to reduction in life chances, stigmatisation and social exclusion. This is particularly so for children and females. Visceral leishmaniasis is responsible for 20,000-40,000 deaths each year, mainly in Sudan, Bangladesh, Nepal, India and Brazil. In addition to the health impact, the leishmaniasis affect economic development in LMICs, with extensive stays in hospital and / or treatment costs having a considerable impact for patients, their families and for affected communities. Knowing why current drugs work better in some people and in some countries than in others and the ability to use this information in rapid point of care clinical decision making would have a major impact on patient health and help reduce the economic burden of disease.

This proposal sets the foundation for a longer more far reaching program of work that aims to reduce the burden of leishmaniasis in LIMCs. The step change in research approach that we are proposing will provide clinicians and researchers with much better access to clinical materials, taken during routine diagnosis, than has ever been possible before. In depth analysis of these samples using state of the art "omics" approaches will generate new knowledge and help us develop new tests to guide clinicians on the most appropriate treatment, improving individual patient experience, and reducing direct and indirect treatment costs. The manufacture and marketing of these tests would provide new commercial opportunities in LMICs.

The technology we will use to develop an internet based tele pathology network will extend the developments in telehealth already underway in some LMICs and demonstrate its added value for research and health practice related to not only leishmaniasis but other neglected diseases of poverty.
This will foster greater adoption of this approach for clinical decision making, research and importantly for education and training. We believe that the use of new technology in this way will encourage young researchers and clinicians to make their careers in the field of poverty related diseases. We see leishmaniasis as an exemplar of what might be achieved across a range of poverty related diseases.

By conducting a health economic evaluation of the value added by developing global networks for research and training and by developing point of care testing to aid therapeutic choice, we will enhance the case for future research and uptake of such practices by health service providers. Evidence of greater research capacity and translational impact will also encourage further funding into these diseases in LMICs by major funders such as the Wellcome Trust and or BMGF, as well as through the GCRF.