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

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Inflammation Research

Abstract

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.

Technical Summary

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.

Planned Impact

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

Publications

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Barr LC (2013) A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation. in American journal of respiratory and critical care medicine

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Brazil TJ (2014) Constitutive apoptosis in equine peripheral blood neutrophils in vitro. in Veterinary journal (London, England : 1997)

 
Description IRC award (Bradley/Dhaliwal/Haslett)
Amount £11,600,000 (GBP)
Funding ID EP/K03197x/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 10/2013 
End 09/2018
 
Description Molecular endotyping lung fibrosis
Amount £80,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 08/2020
 
Title MMP sensing 
Description Novel method of measuring MMP activity 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Novel method of sensing MMP activity in human tissue 
 
Title Edinburgh lung fibrosis cohort 
Description Unique cohort of incident consecutively presenting cases 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact Unique description of natural history of lung fibrosis 
 
Description Cleveland Clinic 
Organisation Cleveland Clinic
Country United States 
Sector Hospitals 
PI Contribution Developing a collaborative partnership to expedite the implementation of optical molecular imaging in the USA and in particular in respiratory medicine. Exchanging ideas, projects and clinical protocols for the Cleveland Clinic to begin initiating an optical imaging programme in Respiratory Medicine using imaging agents developed in Edinburgh
Collaborator Contribution Access to patients and clinical network input to initiate clinical trials.
Impact The Cleveland Clinic has successfully received an eIND from the FDA to perform clinical studies using imaging agents that have been developed by the team at Edinburgh.
Start Year 2015
 
Description Guys 
Organisation Guy's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Developing a sterile fill collaboration with the Guys NIHR facility
Collaborator Contribution Providing academic rates for sterile fill GMP production so that we can complete clinical studies
Impact Successful GMP manufacture of optical imaging agents for clinical trials
Start Year 2014
 
Description Mauna Kea Technologies 
Organisation Mauna Kea Technologies
Country France 
Sector Private 
PI Contribution Developing a delivery catheter to deliver optical imaging agents to the distal lung. We tested prototypes, contributed to the risk assessment and also are performing the initial clinical trials of the catheter
Collaborator Contribution Manufacture, quality management systems , sterility validation
Impact Development and delivery of 40 clinical catheters to our group.
Start Year 2013
 
Description Pharmaceutical Industry 
Organisation UCB Pharma
Department UCB Celltech
Country United Kingdom 
Sector Private 
PI Contribution Providing samples and reagents
Collaborator Contribution Providing descriptions of development pathways
Impact none yet
Start Year 2015
 
Title OPTICAL PROBE FOR THROMBIN 
Description Optical probes are presented, the probes comprising a first probe element, and a second probe element connected to a core. The first probe element comprises a first fluorophore connected to a first quencher by a first cleavable linker. The second probe element comprises a second fluorophore connected to a second quencher by a second cleavable linker. The first fluorophore is separated from the first quencher when the first cleavable linker is cleaved, and the second fluorophore is separated from the second quencher when the second cleavable linker is cleaved. 
IP Reference WO2016151297 
Protection Patent granted
Year Protection Granted 2016
Licensed No
Impact During the award, two patents to protect both the MMP probe (FIB ONE) and another lead candidate (Thrombin) have now been filed by the University of Edinburgh. These patents also incorporate the dual probe (FIB TWO). The filed IP and data from the first clinical study is ready for licensing to optical imaging companies. During the tenure of this DPFS award, the investigation team spun out a company (Edinburgh Molecular Imaging) which is in negotiation with the University of Edinburgh to licence the IP of these lead compounds as we move forward in development. Since submitting the final study report, we have not generated any new exploitable data but are exploring ways in which this Smartprobe can delineate cancer margins in surgery.
 
Title OPTICAL PROBES FOR MATRIX METALLOPROTEINASES 
Description An optical probe is presented comprising at least one fluorophore connected to at least one quencher by an enzyme cleavable peptide sequence; the or each fluorophore being substantially fluorescently quenched by the at least one quencher when connected to the enzyme cleavable peptide sequence;the or each fluorophore is separated from the at least one quencher when the enzyme cleavable peptide sequence of the at least one probe element is cleaved; and the enzyme cleavable peptide sequence is selectively cleavable by one or more matrix metalloproteinase (MMP). 
IP Reference WO2016151299 
Protection Patent granted
Year Protection Granted 2016
Licensed No
Impact During the award, two patents to protect both the MMP probe (FIB ONE) and another lead candidate (Thrombin) have now been filed by the University of Edinburgh. These patents also incorporate the dual probe (FIB TWO). The filed IP and data from the first clinical study is ready for licensing to optical imaging companies. During the tenure of this DPFS award, the investigation team spun out a company (Edinburgh Molecular Imaging) which is in negotiation with the University of Edinburgh to licence the IP of these lead compounds as we move forward in development. Since submitting the final study report, we have not generated any new exploitable data but are exploring ways in which this Smartprobe can delineate cancer margins in surgery.
 
Title FIB ONE 
Description The FIB ONE compound is based on an Aminomethyl Chemmatrix resin linked to three 5- carboxyfluorescein (FAM) molecules via a Rink Amide linker. The FAM molecules are bonded to three quenchers (Methylred) by a peptide sequence acting as substrate for the target enzyme (MMP 2/9/13). In the inactive state, the emission from the fluorophore moiety is absorbed by the quencher by Förster Resonance Energy Transfer (FRET), but in the presence of the target enzyme this can cleave the substrate disrupting the FRET and causing a rapid increase in fluorescence. We have obtained all of the relevant approvals to run our proof of concept study and it is thought that this will begin in March 2016. All updates on this have been provided in the end of project report. 
Type Diagnostic Tool - Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact The development of FIB ONE will be used to develop a novel approach to address the unmet needs of identifying and measuring the pulmonary fibroproliferative pathway. 
 
Title Triple Lumen Bronchoscopic Delivery Device 
Description This device was developed with Mauna Kea Technologies as part of a MICA award from the DCS award. The catheter has gone through extensive testing and has now been delivered to Edinburgh for clinical testing. It is a unique triple lumen catheter that is less than 1.7 mm in diameter and can access the working channel of the bronchoscope. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact New collaboration with the University of Utah - Professor Bob Hitchcock. Dept of Engineering. Novel applications have led to GSK being interested in using the device for pulmonary drug deposition studies and a GSK investigator led study is now being planned. 
 
Company Name Edinburgh Molecular Imaging 
Description SME that is focussing on Optical Molecular Imaging and the rapid commercialisation of in vivo optical imaging agents for human disease 
Year Established 2014 
Impact Raised £4M Series A. Awarded Innovate UK award.
Website http://www.edinimage.com