UKRMP Safety Hub

Lead Research Organisation: University of Liverpool
Department Name: Institute of Translational Medicine

Abstract

Context of the Research

The emerging field of Regenerative Medicine Therapies (RMTs) has the potential to transform medicine and provide treatments and cures in areas of unmet need that are intractable to current practice. There are growing numbers of clinical trials in areas as diverse as stroke, heart disease and cancer. However, with all emerging technologies, there are a number of barriers that need to be addressed, one of which is safety. The focus of our research programme will be to provide a clearer understanding of the potential hazards (and associated risks) with RMTs, so that scientific stakeholders (academics, clinicians, pharmaceutical companies, biotechnology companies, regulatory authorities) are able to accelerate these new medicines into the human population with full confidence.
Of particular importance, is the need to be able to monitor and track cells when they are transplanted into patients to assess whether any of the cells take residence in inappropriate areas of the body. This is essential because inappropriate distribution of RMTs could lead to unknown (and potentially serious) side effects. However, current methodologies used to monitor the biodistribution and behaviour of transplanted cells over time are not capable of providing the sensitivity or specificity required.
Certain types of labels that show promise in tracking RMTs are nanoparticles which act as contrast agents for different imaging techniques (such as magnetic resonance imaging, MRI) and a number of these nanoparticles have been approved for clinical use. However, they do not currently display the necessary characteristics for the sensitivity that is required to track transplanted cells.

The new technologies we need have to be developed in a way that ensures that they are accepted by the professionals in industry and the health service who will be responsible for deploying them. Our project therefore features an ongoing detailed dialogue with these stakeholders to define the hazards associated with regenerative medicine therapies and gain acceptance for the protocols we will develop to ensure these therapies are safe.

Aims and Objectives

1. We will engineer long-term stable nanoparticles with superior signal intensity, uptake behaviour, stability and retention to the current commercial benchmark

2. We will evaluate these nanoparticles in laboratory tests to ensure that, once they are introduced into human cells, they do not cause damage or change in function to the cells.

3. Labelled cells will then be tracked in rodent models of liver or kidney damage using a collection of cutting-edge imaging techniques to determine a) the most appropriate imaging technique to use; b) the sensitivity of the labelled cells and; c) where the cells are distributed in the body

4. With a clearer knowledge of distribution of the introduced cells (the hazard), we will be able to evaluate potential safety risks.

5. Using different transplanted cells, different imaging techniques and improved cellular labels, we will define a generic roadmap for the most appropriate label/imaging combination that should be used to evaluate RMT biodistribution.

6. We will work with a commercial partner to progress the best nanoparticle into formal development so that it will be ready for downstream clinical applications.
Potential Applications

The Safety Hub will, for the first time, provide a clear framework for the most appropriate label and imaging technology to use for robust safety assessment of RMTs. The benefits will be felt by beneficiaries involved in the development of novel RMTs that will ultimately lead to acceleration of these therapies into a clinical setting.

Technical Summary

We will conduct facilitated stakeholder engagement through a series of workshops and reports, informed by experimental progress in this and the partner Hubs, to develop a consensus on how best to assess whether a new regenerative medicine therapy is safe in man. Synthesis of tracking particles (SPIONs, gold nanorods) and development of associated polymer coatings to ensure stability, long-term retention and optimised imaging performance for MRI and photoacoustic imaging (plus multimodal imaging) will build on our recent demonstration of systems exceeding commercial benchmarks. Evaluation of emergent 19F methods will take place and, if warranted, developed further. Reporter genes will be used to indicate cell viability in combination with the nanoprobes. Nanoprobe viability and safety will be assessed with KSPCs, macrophages and HLCs. Biodistribution will be monitored by whole animal imaging in kidney (FA tubular and ADR glomerular) and liver (CCl4 liver fibrosis: macrophage- and ESC-based therapy) disease models. We will assess the biological response of both target and non-target tissues, using organ-selective translational biomarkers of toxicity e.g. mir-122 for liver and Kim-1 and NGAL for kidney, which will link the animal studies and subsequent clinical application of the RMTs. We will use hepatic functional markers such as albumin, and markers of hepatic cell death coupled with metabolic function assays. Kidney tissue damage will be monitored by SPECT/PET and MRI coupled with FDA qualified biomarkers of renal toxicity. Inflammation, systemic toxicity, fibrosis, maldifferentiation and tumourigenesis will be assessed. Regular dialogue with Regulators and commercial partners will ensure all regulatory requirements for the utilisation of novel nanoprobes in early clinical trials are met, with a specific focus on macrophage cell therapy to stimulate liver regeneration and reduce scarring in cirrhosis(aimed to progress to a Phase I trial during the grant).

Planned Impact

The UKRMP Safety Hub will develop toolkits and roadmaps for more effective evaluation of safety and efficacy of novel regenerative medicine therapies (RMTs) fit for translation to man. It is anticipated that the Safety Hub will have an impact on a significant number of beneficiaries, although it is important to point out that most of our beneficiary groups will also be stakeholders in our activity, and therefore our relationship with them will be based on dialogue and interaction.
1. Academia
Novel techniques developed in the Safety Hub will have utility across each of the different UKRMP Hubs. Furthermore, academic centres (both nationally and internationally) that are working on novel RMTs will benefit from the Safety Hub output such that the effectiveness and safety of the RMTs can be evaluated more robustly with potential acceleration of translation to man. This will not only enhance the competitiveness of the UK regenerative medicine science-base but will also improve our international standing.
2. Industry
The Safety Hub will potentially impact on a number of industrial sectors. Firstly, Pharmaceutical Companies, facing a growing pressure to diversify portfolios, and moving away from the blockbuster model, are investing in personalised and targeted therapies. Whilst their investment in RMT is currently exploratory rather than exploitative, they will be encouraged to invest in commercialisation if current safety and regulatory hurdles are overcome. Secondly, biotechnology companies that specialise in RMTs will be able to use the Safety Hub toolkits and roadmap to develop more rigorous safety and efficacy data packages for translation to man (and potentially improve partnering opportunities). Thirdly, diagnostics companies and biomedical product companies will see opportunity to commercialise novel imaging technologies and/or contrast agents developed by the Safety Hub in their core business - this will likely include diagnostic imaging applications in addition to RMT
3. Public Sector
A significant (and early) beneficiary will be the Regulatory Authorities who will learn from findings generated in the Safety Hub in order to improve regulation in what is an emerging technology area. Advances made by the Safety Hub will have potentially transformative benefits for the NHS in the long-term as the safety framework increases confidence in the field and accelerates its maturity, leading to more rapid and confident uptake of therapies in clinical practice.
4. Third Sector.
As identified in the BIS document "Taking Stock of Regenerative Medicine in the United Kingdom", charitable investment in RMTs was approximately 20% of public funding between 2005 and 2009, a figure that is broadly typical of an emerging technology. As the RMT field matures, and as the impact of the Safety Hub is felt, it is anticipated that charitable funding in RMTs will increase significantly.
5. General Public.
The Safety Hub will have both a societal and health & wellbeing impact on the General Public. By defining the hazards associated with RMT biodistribution we will be able to develop more effective risk-benefit metrics for translation to the clinic which, in turn, will allow the UK RMT community to communicate these risks and benefits more effectively to the General Public through media engagement, meetings with patient groups, lay people and ethics groups. This will significantly enhance the on-going societal debate on RMT. In the longer term, and aligned with benefits to the NHS, the maturation of the RMT field will have significant health & wellbeing implications to the General Public as once intractable diseases or conditions become treatable.

Publications

10 25 50

 
Description Horizon 2020
Amount € 134,467 (EUR)
Funding ID 705600 - MultimodalCellTrack 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 08/2016 
End 07/2018
 
Description Kidneys for Life
Amount £15,000 (GBP)
Organisation Kidneys for Life 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2016 
End 12/2016
 
Description Kidneys for Life Research grant
Amount £10,000 (GBP)
Organisation Kidneys for Life 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2018 
End 12/2019
 
Description Project Grant funding
Amount £7,931 (GBP)
Organisation Kidneys for Life 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2018 
End 12/2019
 
Description Stoneygate Feehally research award
Amount £251,813 (GBP)
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2017 
End 04/2020
 
Description UKRMP Capital Equipment Call
Amount £3,307,918 (GBP)
Funding ID MR/L012707/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2014 
End 03/2015
 
Description UKRMP II Systems-focussed Programme.
Amount £3,000 (GBP)
Funding ID MR/L022893/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2014 
End 10/2017
 
Title 5Xluc and bicistronic vector 
Description Applicaiton of new vesctors suitabel for invivo imaging to hESC and their use in differentiation 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Following safety toxicity testing etc initiaion of use in invivo repair strategies 
 
Title GFP labelled human ESCs 
Description Human ESCs were labelled with GFP using lentiviral vector. 
Type Of Material Cell line 
Provided To Others? No  
Impact These cells could be used for studies requiring tracing cell migration or destination. 
 
Description David Long 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We are training people from the Long lab in PSC culture, iPSC derivation and differentiation into kidney progenitors
Collaborator Contribution Collaboration over mutant kidney phenotype in PkD
Impact Training
Start Year 2017
 
Description MSOT User Group 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution MSOT (Multispectral Optoacoustic Tomography) is a new technology; build an effective UK community to enable sharing of best practices and protocols.
Collaborator Contribution Establish UK MSOT technology base and community
Impact Biannual meetings
Start Year 2014
 
Description MSOT User Group 
Organisation iThera Medical
Country Germany 
Sector Private 
PI Contribution MSOT (Multispectral Optoacoustic Tomography) is a new technology; build an effective UK community to enable sharing of best practices and protocols.
Collaborator Contribution Establish UK MSOT technology base and community
Impact Biannual meetings
Start Year 2014
 
Description ASW Schools talk 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Xaverian College Manchester talk Making new human kidneys
Year(s) Of Engagement Activity 2019
 
Description ASW family information day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact HNF1B/Renalcysts and diabetes syndrome Family Information day Bristol
Year(s) Of Engagement Activity 2018
 
Description ASW industrial outreach 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Kidney Research UK Outreach Event at Chiesi HQ Manchester
Year(s) Of Engagement Activity 2018
 
Description ASW schools 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Manchester Schools' Outreach programme Growing human kidneys
Year(s) Of Engagement Activity 2018
 
Description Imaging for biodistribution, function and safety assessments of the liver 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact To address the issue of how imaging can provide better understanding and prediction of drug-induced liver injury, a workshop was hosted by the UK Regenerative Medicine Platform Safety and Efficacy Hub and the MRC Centre for Drug Safety Science Workshop comprising 42 attendees made up of local and national academics, including representatives from industry (both national and Europe) and MHRA.
Year(s) Of Engagement Activity 2017
 
Description Public /patient engagement 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Update on kidney disease and reviw of how research is making progress in the area
Year(s) Of Engagement Activity 2016
 
Description Stem Cells and Regenerative medicine from chondrocytes to kidneys 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talk on Regenerative medicine to U3A members
Year(s) Of Engagement Activity 2018
 
Description UKRMP Safety Hub Quarterly Newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Awareness of research ongoing within the Safety Hub for stakeholders, Industry, other academics.

Too early to say
Year(s) Of Engagement Activity 2014
URL http://www.ukrmp.org.uk/hubs/safety/newsletters/
 
Description What is Regenerative Medicine? 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact A workshop to inform Undergraduates about what regenerative medicine is and how t can expand the possibiites for Medicine ( based on our successful workshop in 2017)
Year(s) Of Engagement Activity 2018
 
Description Women in Science Becoming the Best 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Dissemaination of information advice and support for women's role and leadership in scince
Year(s) Of Engagement Activity 2016
 
Description infomation day for kidney patients and professionals 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Information day on kidney disease and research addressing this for patients
Year(s) Of Engagement Activity 2016