Pre-clinical In-vivo Functional Imaging for Translational Regenerative Medicine

Lead Research Organisation: University of Bristol
Department Name: Clinical Science at South Bristol

Abstract

Acquired or congenital diseases can cause marked damage in organs (heart, muscles, bones, brain, liver, vessels, etc) and represent a huge burden on health outcome and NHS costs (over £1bn/year in the UK). Currently, it is possible to send these sick patients for special scans that allow doctors to gather fine details about the type of damage and the degree of loss of function in diseased organs. It is based on the outcome of these scans that most of the treatments are initiated in patients.

Stem cell researchers carry out experimental pre-clinical work in fish, mice, and/or pigs models of disease to attempt restoring organ structure and function to rectify disease. This is done with a view to use these new discoveries to treat sick patients. However, in this stem cell experimental research most of the scientists are still looking at histology i.e. the animals are sacrified and samples from relevant organs are analised under the microscope to ascertain if treatments have been safe and/or effective. Although this approach is valuable, the information gathered from it has poor relevance to how the type and extent of disease is evaluated and measured in patients. This lack of alignment in methos of evaluation between experimental and clinical research is an issues in the UK and it leads to poor applicability of experimental knowledge to patients and to obvious delays in bringing new stem cell treatments to the bed side.

Performing quality in-vivo imaging scans in animals undergoing stem cell research treatments (similar to the imaging scans done in patients) will provide key clinically relevant information on safety and efficacy boosting and fast-tracking its application in patients.
At the University of Bristol we have world class espertise in stem cell research spanning from outstanding experimental work to several world first trias in patients with cardiac, brain and muscle-skeletal severe disease. We now wish to invest in quality pre-clinical in-vivo imagingto increase our changes to bring new experimental discoveries in stem cell research into the NHS for the benefit of patients. We are requesting four in-vivo imaging items for our experimental platform including: (i) a multi-photon microscope, a special microscope that allows to track stem cells live in zebrafish; (ii) a micro positron emission tomography, a modern scan that track stem cells and small particles in mice in-vivo; (iii) a micro-computed tomography, a key type of in-vivo scan allowing to image the damage in whole organs; (iv) and a 3T magnetic resonance imaging, a special scan that allow to measure in-vivo in pig the amount of organ damage and its impact on function; and how this is affected by stem cell therapies. We have already in our clinical NHS settings similar quality imaging for our patients; hence these four imaging items for our pre-clinical work will allow synergic alignment.

Thanks to these items we will be able (i) to establish the immediate fate of stem/progenitor cells (on the day of delivery); (ii) to improve modes of cell delivery and retention in the damaged area; (iii) to establish the long-term effect of these novel therapies (weeks to months); (iv) to design design experimental studies using the same scan-based measures used in patients; (v) in additon, by taking in-vivo imaging scan we will be able to follow up the same animal in the long-term, hence reducing makedly the number of animals to be sacrified.

Technical Summary

Basic science knowledge in regenerative medicine is still mostly histology-based with poor longitudinal in-vivo imaging. Hence, its clinical relevance remains poor. Our objectives and overall strategy is to invest in four modern in-vivo functional imaging technologies for our pre-clinical experimental models with strategic alignment to the imaging already available for our research patients. This will boost translation by transforming the available histology-based knowledge into the functional, longitudinal imaging-based knowledge that drives modern clinical practice. To this end we request: a multi-photon microscope for zebrafish, a micro-CT and a micro-PET for mice, and a 3T-MRI scanner for large animal (pig, sheep). The latter item is in synergy with our other project of establishing a unique in the UK large Translational Biomedical Centre (TBC) for large animal also including two GLP surgical theatres (one hybrid with a biplane angiography imaging suite), a GLP lab, two sponsor rooms for academic partnerships with biomedical industry and research office space. The plan is to house the TBC on our Veterinary Science School campus in Langford. Our TBC project is in line with the outcome of the recent MRC-BHF Cardiovascular Working Group Meeting.

At academic and regulatory level, one of the pressing needs to facilitate translation in regenerative medicine is to obtain clinically relevant longitudinal in-vivo imaging monitoring and tracking of cells to ensure effective delivery, quantify cell engraftment/homing, and retention; thereby informing patient safety. In addition, the long-term functional impact of cell delivery, measured in-vivo with clinically relevant technology, is as critical as demonstrating engraftment and residency to inform efficacy, hence translation.

Planned Impact

The pre-clinical in-vivo functional imaging platform for translational regenerative medicine will be of benefit widely to the UK academic and bioscience industry.

It will complement existing imaging facilities with strategic alignment to our clinical imaging facilities (3TMRI scanner in CRIC, a 1.5T MRI scanner in NIHR Cardiovascular Disease BRU in Bristol, PET research facilities in Cardiff). This will be unique in the UK and will have locally a boosting effect of our ability to translate while triggering interdisciplinary cross fertilisation.

At national and international level we will consolidate our leadership while providing a reference platform for multicentre studies for our collaborators.

Further downstream the public will benefit from the research that this suite of equipment will enable as it clears the current bottle necks in translation of fundamental regenerative medicine research into the clinic and to patient benefit.

Publications


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Ascione R (2016) Bridging the Gap in Heart Matters
Gadeberg HC (2016) Heterogeneity of T-Tubules in Pig Hearts. in PloS one
 
Description Establishment of the Translational Biomedical Research Centre as a national facility for large animal research operating at GLPMA and NHS standards
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.bristol.ac.uk/health-sciences/research/tbrc/
 
Description A Polymeric Prosthetic Heart Valve from anisotropic nanocomposites- device optimisation and in vivo testing
Amount £755,030 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Description BHF Infrastructure bid toward TBRC
Amount £998,000 (GBP)
Funding ID BHF Infrastructure Grant IG/14/2/30991 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2014 
End 01/2016
 
Description Funding toward enhancing the new Translational Biomedical Research Centre (TBRC)
Amount £998,912 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Description MRC Capital Bid in Regenerative Medicine 2013 call
Amount £2,770,000 (GBP)
Funding ID MR/L012723/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2014 
End 03/2016
 
Description Selective S-nitrosation of mitochondrial complex I by MitoSNO as a new therapy for cardiac ischaemia-reperfusion injury
Amount £792,560 (GBP)
Organisation MRC-UK 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Title Contribution towards the Translational Biomedical Research Centre 
Description This award has allowed us to purchase a 3T MRI scanner for large animals to be housed in the Translational Biomedical Centre that we are developing under my leadership at the University of Bristol. This is a facility of international relevance with GLP/GMP standard across this whole package of specifications. This facility will open in Spring 2015 and will be available to any UK researchers in line with our discussion with the MRC and BHF who have co-funded this initiative together with the University of Bristol. 
Type Of Material Improvements to research infrastructure 
Year Produced 2014 
Provided To Others? Yes  
Impact As academic lead of the facility I have been contacted by several UK researchers from Oxford, Cambridge, Edinburgh and London who are considering undertaking advanced large animal research work at our facility including work in the regenerative medicine field. A collaborative grant with Cambridge has already been submitted. 
 
Description BHF 4-YEAR PhD PROGRAMME: Integrative Cardiovascular Science 2017-2020 (PI A Poole; Co-PIs R Ascione, et al) 
Organisation University of Bristol
Department School of Physiology & Pharmacology Bristol
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Contributed to write the grant application with a focus on the translational research in large animala including small research packages at TBRC facility as well as clinical aspects and working experiences for the students
Collaborator Contribution Collaborative approach to grant drafting and submission from basic scientists including PI and co-PIs
Impact The BHF PhD programme started this year. At the initial year-1 student selection process a project submitted by myself has been selected by a student who was then selected for the position for 2017-2020.
Start Year 2017
 
Description Call H2020-ICT-2016-1; SMart weArable Robotic Teleoperated Surgery (SmartSurg). 
Organisation Bristol Robotics Laboratory
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution I have contributed to the successful grant application and written the cardiovascular section including a package of work at TBRC based on the development of the new smart surgical instruments. This is a pan-european collaborative project including experts in biomedical robotics, computer science, on-body sensors, smart glasses, and clinical scientists from other clinical areas including urology and muscle-skeletal.
Collaborator Contribution Providing robotic expertise and dedveloping prototypes based on clinical feedback from each of the three clinical user areas
Impact We have had starting meetings, created a web site going live soon and had a formal press release (to be released on 13 March 2017)
Start Year 2017
 
Description Collaboration with Cambridge (Dr Mike Murphy) on the novel cardioprotective drug MitoSNO 
Organisation University of Cambridge
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution This collaboration has led to a joint grant to the MRC led by Dr Mike Murphy in Cambridge with myself being the Bristol lead. The grant is about the efficacy of mitoSNO in reducing myocardial ischemia reperfusion injury following MI. My contribution is in leading and performing the large animal work at the Translational Biomedical Research Centre (TBRC), a unique in the EU facility for large animals (pig/sheep), operating at NHS, Home Office and GLPMA standards, that I have set up at the University of Bristol Veterinary Sciences campus in Langford which is co-funded by the MRC through this award (£1.7M to purchase a 3T MRI scanner) for a total cost of of £5.5M, now also including £1M fro the BHF. My role will be to induce acute MI in pig and test the dose-dependent safety and efficacy of the new drug based on MRI longitudinal imaging over 4 weeks post MI to mimic NHS approaches. We submitted the application to the MRC in 2014, in which I designed the large animal milestone. Currently, there is a milestone ongoing in Cambridge on optimising the production of the new drug in the lab and in small rodents. In the mean time I have applied for a Home Office licence. The in-vivo testing in pig is due to start in summer 2016.
Collaborator Contribution My partners in Cambridge developed the new drug and tested it in small animals/rodent models of ischemia-reperfusion injury. They now need to validate the efficacy and safety of this drug in large animal models. If this work is effective we will move together into a first in man trial.
Impact This collaboration has led to the following successful grant award by the MRC in 2014: 2015-18: Selective S-nitrosation of mitochondrial complex I by MitoSNO as a new therapy for cardiac ischaemia-reperfusion injury. PI M Murphy (Cambridge); co-PI R Ascione (Lead in-vivo study at TBRC-Bristol), T Krieg, A Mander (Cambridge), R Smith (Otago -NZ); MRC: £792,560 This is a multidisciplinary translational collaboration involving Cardiac Physiology, Pharmacology, Cardiac Surgery, and Industry.
Start Year 2014
 
Description Collaboration with Cambridge (G Moggridge) on testing a new heart valve 
Organisation University of Cambridge
Department Department of Chemical Engineering and Biotechnology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution This project is about testing in a porcine large animal model of cardiac surgery at the new Translational Biomedical Research centre for large animal I have set up at the University of Bristol (co-funded by MRC, BHF, and UoBristol for a total of £5.5M) the safety and efficacy of a new heart valve made from a polymeric anisotropic nanocomposites. We submitted a Special Project Grant (led by Dr Geoff Moggridge, UoCambridge) to the BHF for £755k which was awarded in 2015. My collaborators have no clinical background , hence with no expertise in testing such a device in-vivo with a view to a first in man trial. My contribution in this collaboration has been to provide advices on the design of the valve made from the new polymeric material and then conceive, design and included in the application a working package fully based at the TBRC under my leadership to implant these new heart valve in a porcine model of cardiac surgery with cardiopulmonary bypass and cardioplegic arrest; also including recovery up to 6 months. At present there is a working package being developed in Cambridge aiming to refine the design of the new valve to facilitate its surgical implantation, also based on my clinical feedback. The multidisciplinary team meets regularly. I am applying for Home Office licence in preparation for my working package testing the valve in an in-vivo model, which is due to start in January 2017.
Collaborator Contribution My partners have developed the new polymeric material, used a mould to make a heart valve being tested in the lab in a pulse accelerator mechanical device. This has been done in collaboration with the Politecnico di Milano and the University of Tubigenen.
Impact This collaboration has led to teh award of a large project grant as follows: 2015-19: A Polymeric Prosthetic Heart Valve from anisotropic nanocomposites- device optimisation and in vivo testing. PI G Moggridge (Cambridge); co-PI R Ascione (Lead in-vivo study at TBRC), MS Suleiman, N Sukumaran, A Zaman. BHF Special Project Grant: £ 755,030 This is a multidisciplinary collaboration involving a team of experts spanning Chemical Engineering and Biotechnology, Mathematical Modelling, Cardiac Physiology, and Cardiac Surgery.
Start Year 2014
 
Title Cardioprotective drug MitoSNO 
Description This is a new cardio-protective drug to be tested in an acute MI model in pig at the new TBRC facility in Bristol. This is part of a collaborative work with the University of Cambridge (lead Dr Mike Murphy), University of Otago (NZ) and University of Bristol with myself leading the translation of the new drug via an experimental trial in pig to test its safety and efficacy prior to a first in man trial. This work was funded by BMC: DPFS: MR/M015769/1 in 2014 as follows: 2015-18: Selective S-nitrosation of mitochondrial complex I by MitoSNO as a new therapy for cardiac ischaemia-reperfusion injury. PI M Murphy (Cambridge); co-PI R Ascione (Lead in-vivo study at TBRC), T Krieg, A Mander (Cambridge), R Smith (Otago -NZ); MRC: £792,560 Currently, the new drug is undergoing refinements with extra test in vitro and in mice in Cambridge. The large animal milestone is due to start in Bristol during summer 2016. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact This work has led to the formation of an effective multidisciplinary team in this clinical field. This has triggered the same team submitting a further large grant application to the Sir Jules Thorne scheme in 2015. This application is based on the testing the safety and efficacy of a new cardio-protective drug based on the use of malonate esters for myocardial protection during cardiac surgery. This application has been recently accepted as an outline and we have been asked to submit full application with by April 2016. 
URL http://www.manufacturingchemist.com/news/article_page/UK_Government_commits_over_30m_to_cutting_edge...
 
Title Novel clinical platelet analyser 
Description NHS FSF Bristol: £20k 
Type Therapeutic Intervention - Medical Devices
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact TBC 
 
Description Formal opening of the TBRC facility for large animal by MRC Chief Scientific Officer and BHF Medical Director in June 2016 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The TBRC formal opening was marketed with a formal Ceremony attended by regional and national stakeholders. A brochure was sent to the national network of >300 members as well as biomedical industry. Talk at institutional and public events were arranged during the same time period for transparency and to increase awareness. This was associated with a national press release. In addition, the BHF wrote a 3 page article fostering Prof Ascione in their "Heart Matters" magazine which is distributed in approx 3.5million copies to any research and NHS institutions across the UK as well as including it on their website. A TBRC website was opened at: http://www.bristol.ac.uk/health-sciences/research/tbrc/
Year(s) Of Engagement Activity 2016