In vivo imaging technologies to assess the efficacy and safety of regenerative medicine therapies

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

Abstract

The emerging field of Regenerative Medicine Therapies (RMTs) has the potential to transform medicine, enabling the development of effective treatments in areas of unmet clinical need that pose intractable problems in current practice. Clinical trials of RMTs are already being carried out in diseases as diverse as stroke, heart disease and cancer. However, all novel clinical technologies face a fundamental question: are they safe? The aim of our research programme is to develop methods to answer this question, first in animal models, and then in experimental human studies. A better understanding of the potential hazards of RMTs, and the development of practical tools to assess them, will underpin the safe, confident introduction of these new medicines into clinical use.

RMTs typically involve transplanting cells into patients. It is especially important to be able to monitor where they go in the body (their biodistribution), because inappropriate distribution could lead to potentially serious side-effects. Current methods used to monitor the biodistribution and behaviour of transplanted cells over time are inadequate. One promising approach is the use of labels to track RMTs, for example magnetic nanoparticles (MNPs), which act as 'contrast agents' detectable by imaging techniques such as magnetic resonance imaging (MRI). A number of MNPs have been approved for clinical use. However, with current methods they lack the sensitivity required to track small numbers of transplanted cells over long periods. There is a pressing need to develop MNPs with superior properties that are capable of doing this more effectively.

Monitoring transplanted cells requires a range of different imaging strategies - no single technique provides the full range of information required. MRI can be used in both animals and humans, is entirely safe and has excellent spatial resolution to locate MNP-labelled cells precisely after they have been introduced into the body; its disadvantage is its relatively low sensitivity, which makes it difficult to detect small numbers of cells. By contrast, nuclear imaging techniques such as single positron emission computed tomography (SPECT), which can also be used in animals and humans, are much more sensitive than MRI, enabling them to track much smaller numbers of cells; their disadvantage is their relatively poor spatial resolution, which makes it difficult to precisely locate the cells, and makes it necessary to acquire separate anatomical images by combining with MRI or computed tomography (CT). A further important disadvantage of nuclear imaging techniques is that cells must be 'radiolabelled' with molecules that emit radiation (gamma rays, in the case of SPECT), posing important safety issues for patients; safety could be considerably improved if we had imaging methods of better sensitivity, which would reduce the amount of radiolabel required.

In this project we will take two complementary approaches. First, we will improve our ability to detect MNP-labelled cells with MRI by engineering new MNPs with superior signal intensity and retention properties. Second, we will make a substantial improvement in SPECT scanner performance by exploiting a novel design using a 'Compton camera', which allows more accurate localisation of the gamma-ray source and much greater sensitivity. Importantly, the new SPECT will be designed to operate within the magnetic field of the MRI system so that it will be possible to scan with both techniques at the same time. Using the MRI/SPECT together, with other imaging technologies, we will then use mouse models to define in detail where transplanted cells are distributed in the body and the effect they have on the host tissues and organs. This information will considerably improve our ability to assess which RMTs can safely be used in humans.

Technical Summary

The novel SPECT system that will form the nuclear imaging component of System A (9.4T MRI/SPECT platform, see case for support, CfS) will be specified by the University of Liverpool and will consist of cadmium zinc telluride sensors with an application specific integrated circuit (ASIC) read out and electronics system incorporating a field programmable gate array (FPGA). The design will specify dimensions and materials suitable for use in the 9.4T magnetic field. This MRI/SPECT system will be used to evaluate the short to medium term biodstribution and fate of cells labelled with superparamagnetic ion oxide nanoparticles (SPIONs), and monitor their effect on host tissues. We expect that this system will be capable of dynamic imaging, allowing kinetic modelling of the initial dynamic phase of a bolus injection. System B at UoL, comprising micro-SPECT/CT, fluorescence and bioluminescence imaging (FL/BLI), will primarily be used to evaluate the biodstribution and behaviour of cells expressing nuclear/FL/BLI reporters over the short to long term. System C at UoM, comprising low-field MRI and micro-PET, will primarily be used to evaluate the short to long term biodistribution and behaviour of cells expressing nuclear reporters, but as the benchtop scanner will operate at the field strength of clinical scanners (typically 1.5T or 3T), it will also provide valuable information for translation of MR protocols to the clinic. The enhanced MSOT system at UoL (see CfS), will have additional detectors that will increase spatial resolution. The MSOT has multispectral photoacoustic capability, permitting imaging and consolidation of data from multiple wavelengths; the instrument is thus capable of visualising administered cells (labelled with gold nanorods or expressing a photoacoustic reporter), monitoring their behaviour (e.g. Annexin V-based probes for apoptosis), and evaluating effects on host tissues and organs (e.g. through visualising the vasculature).

Planned Impact

The state-of-the-art equipment we request will significantly enhance the activities of the UKRMP Safety Hub, which has been funded to develop toolkits for more effective evaluation of safety and efficacy of novel regenerative medicine therapies (RMTs) fit for translation to man. The Hub is working towards more accurate tracking of RMTs using a variety of labelling and imaging modalities. The UKRMP capital support will allow us to integrate the measurement of safety and disposition of RMTs to levels of sensitivity and specificity hitherto impossible, and will represent a step-change in capability for the UK regenerative medicine community.
The Safety Hub will have an impact on a significant number of beneficiaries, most of whom will also be stakeholders in our activity.
1. Academia
The new equipment will expedite the development of novel imaging strategies by the Safety Hub, which 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 RM science-base but will also improve our international standing.
2. Industry
This grant will increase the potential impact on a number of industrial sectors. Firstly, Pharmaceutical Companies 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 uplift in imaging capability of the Safety Hub will potentially increase the health & wellbeing impact on the General Public. By defining the hazards associated with RMT we will be able to develop more effective risk-benefit metrics for translation to the clinic which 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, 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

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Draper ER (2018) Aligning self-assembled perylene bisimides in a magnetic field. in Chemical communications (Cambridge, England)

 
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