Molecular Optical Imaging of Key Targets in the Fibrogenic Pathway in Man

Fibrosis, or scarring, is a process which complicates many diseases of the lung and other organs and for which no effective treatment is available. There are currently no ways to detect the activity of fibrosis in human tissues in life.

The ability to specifically monitor fibrosis non-invasively in diseased organs would enable stratification of disease and to personalise treatment as well as facilitate the rapid design and testing of new drugs in patients with 'real disease' without the need for animal experimentation.

This project aims to develop 'smart' probes to detect fibrosis in 'real time' in human tissues. This is achieved by the combined application of 'cutting-edge' technology to perform optical imaging microscopy deep in diseased organs to detect the activity of a tiny dose of a coloured compound which has been designed to specifically detect key events in the fibrotic process. This 'microdose' involves no toxicity or radiation exposure.

This technology will enable us not only to detect fibrosis and develop new drugs for human disease but will also be applicable to scarring diseases in animals. Thus the proposed studies using tissue from donkeys, which have a very high natural incidence of a form of lung scarring which is virtually identical to the human variety, will not only help our human translational pathway, but will also provide the basis of much-needed treatment for sick animals.

Fibrotic diseases of the lung and other organs constitute a heavy burden of morbidity and untimely deaths. Idiopathic Pulmonary Fibrosis (IPF) is diagnosed late (on CT scans/lung biopsy) and has an appalling mortality. It is currently impossible to identify patients with Adult Respiratory Distress Syndrome (ARDS) and other inflammatory lung diseases that are developing secondary fibrosis. Moreover there are no effective therapies for fibrosis despite it being a highly active cellular process which should be accessible to intervention. Part of the problem has been the time required to establish drug effectiveness in vivo and the poor utility of existing biomarkers. The innovative translational pathway detailed herein will create novel active markers of fibrogenesis in situ to rapidly establish early diagnosis and efficacy of much needed new therapies in scarring diseases of the lung and other organs. Supported by a previous MRC 'devolved' DPFS award our team has already synthesised a highly-specific human neutrophil smartprobe which has been validated exhaustively in vitro and in vivo using pCLE and is now in GMP synthesis for human application. From this strong foundation we are confident of achieving the aims of the current application.
KEY GOALS:
1) To allow clinicians to rapidly and accurately determine the presence of active fibroproliferation.
2) To apply cutting-edge bronchoscopic confocal imaging technology (pCLE) partnered with local instillation of highly specific and sensitive 'smart' molecular probes at microdose concentrations (<100 mcg).
3) To generate a novel portfolio of GMP-grade materials for first-in-man validation studies that are commercially valuable.
4) To develop potentially gold-standard methodologies for rapidly assessing the efficacy of new antifibrotic drugs in clinical trials and for patient stratification.

This strategy will accelerate the pharmaceutical development and clinical application of antifibrotics.

Impacts on patients and patient pathways:
Rapid and accurate bedside testing for pulmonary inflammation/fibrosis is a "holy grail" in modern respiratory medicine. Currently clinicians are faced with significant uncertainty in relation to assessing pulmonary fibrosis and evaluating disease activity. Better characterisation of pulmonary fibrosis in real-time provides the potential to target existing and novel therapies and detect early predictors of clinical response. For example, despite negative clinical trials, steroids are still widely used in pulmonary fibrosis. Smartprobes offer the potential to improve the risk/benefit profile of steroid therapy and other existing and new therapies by enabling disease-specific effects to be measured rapidly in the individual patient This has the potential to improve patient health while reducing costs.

Exploitation and Application:
This DPFS programme will deliver vital under-pinning biology and chemistry to help address major medical needs/problems in an international setting. We will explore all avenues for the benefit of the UK's economic competitiveness as we believe the research undertaken is likely to generate new concepts, ideas and research tools. Importantly all applicants have a history of patent protecting appropriate discoveries, working with industry and capitalising on discoveries that have had a positive impact on business. The team established thus understands the importance of IP and its appropriate protection but also realises that specialised assistance (through the University of Edinburgh Research and Innovations office) is necessary in order to evaluate, develop and exploit novel IP arising from the research activities. Indeed the close relationship between the Bradley & Haslett groups with Edinburgh Research and Innovation (ERI) (which seeks to promote the University of Edinburgh's research and commercialisation activities) will allow all commercialisation routes to be explored in a responsive and dynamic manner.

Wealth creation for the public:
The teams view is that spinout is a realistic option and has the greatest potential to develop these probes (and in the longer-term additional probes) providing services, probes for preclinical validation, collaborative R&D, but most importantly clinical probes. The Edinburgh BioQuarter is an ideal site for the new company venture as it is adjacent to the hospital and it has recently appointed Dr Capaldi as the new director whose singular purpose is to support company formation. The team also have a strong pedigree in this area, thus Professor Bradley has been involved with a number of spinouts. This includes co-founder of Ilika Technologies (2004)(floated on the London Stock Exchange 2010), Altrika Technologies (2009) and Deliverics (2010). Professor Bradley is an inventor on some 15 patents with a strong record of exploiting IP. Professor Haslett was the first to recognise the translational opportunities offered by PET imaging of FDG as well as F-18 cis-proline in man as well as being the inventor on the UoE patent based on the use of Roscovitine in inflammation.

Research Partnership:
This is clearly a multi-disciplinary activity, requiring the creation of a team of researchers with the necessary expertise and experience in their individual disciplines to realise the opportunities and address the challenges. The University of Edinburgh will benefit from the creation of such a team in terms of their international standing, building of interdisciplinary links, and their ability to attract future funding and industrial support.

Developing Entrepreneurship:
Many optional training opportunities will be available to the scientists through existing mechanisms. The Scottish Institute for Enterprise provides training and support in entrepreneurship and business skills. This is in line with the objectives of the RCUK to develop entrepreneurship within the academic culture and the development of enterprise skills