Generation of Multi-Modal Imaging Mesenchymal Stem Cells

Context of the Research

Regenerative Medicine has the potential to transform medicine and provide treatments and cures in areas of unmet need. Cell therapies using mesenchymal stem cells (MSCs) are increasingly applied in clinical trials in areas such as stroke, heart disease and as adjuvant therapies for cancer. However, with all emerging technologies, there are a number of barriers to evaluating their potential effectiveness that need to be addressed, which is localised delivery to target tissue and functionality of the cells once in situ. The focus of my research programme will be to provide multi-modal cell labelling agents for complimentary imaging technologies that can be utilized together to provide a clear understanding of the mechanisms of delivery and uptake with functional cell survival so that scientific beneficiaries (academics, clinicians, pharmaceutical companies, biotechnology companies, regulatory authorities) are able to accelerate these new medicines to other areas of regenerative medicine as well as translation to the human population with full confidence.

The monitoring the delivery and tracking the viability of cells once transplanted into patients is of particular importance not only for the assessment of both the degree and duration of therapeutic efficacy but also for patient safety. Identification of the optimal route of administration, the degree and longevity of cell uptake and routes of clearance can identify possible organs of risk while potentially limiting the number of repeat injections or surgeries required per patient.

Iron oxide nanoparticle have shown promise in localizing stem cells to defined areas of disease by magnetic resonance imaging, MRI) and a number of these nanoparticles have been previously been approved for clinical use. However, they do not currently display the necessary characteristics for the sensitivity that is required to track transplanted cells or provide information on their functionality in vivo. However, other imaging modalities such as nuclear medicine (SPECT/CT) are capable of tracking cells throughout the body, albeit with poor resolution and with new developments in molecular biology are capable of assessing cell viability in vivo. However, at present one imaging modality and one imaging probe cannot provide the information required for the complete characterization of cell therapeutics.

The new technologies we propose therefore combines innovative molecular biology approaches with nanochemistry to generate multi-modal imaging MSC for in vivo imaging with complimentary preclinical imaging modalities (MRI, SPECT/CT, photoacoustic and bioluminescent imaging). We aim to label cells with both reporter genes and nanopartlces, uniting imaging platforms and imaging probes to utilize the most favourable components of each while reducing their limitations. We will then utilize this to quantify delivery and monitor the localisation and viability of transplanted cells to clinically relevant models of tumours. We will identify the optimal routes of administration and the longevity of cell survival and apply this knowledge to optimize the subsequent application and dosing regimens of our therapeutic MSCs as anti-cancer delivery vehicles. Although this proposal is based on stem cells as adjuvant therapies for cancer the use of our labelling technologies for cell trafficking can be applied to other stem cells and regenerative medicines. Merge this with clinically translatable MR imaging endpoints to provide a full assessment of the efficacy of the cell therapy will therefore accelerate these therapies into mainstream clinical practise.

The work proposed here addresses the current barriers that are essential for the clinical translation of stem cell therapies to the clinic. The ability to accurately track stem cells to their target site and monitor their cell integrity over time by providing important molecular biology and nanoparticle tools for imaging regimes it is anticipated that this proposal will an impact on a significant number of beneficiaries.

1. Academia: Due to multi-disciplinary approach of the proposal the novel techniques developed in will have a direct benefit for academic centres (both nationally and internationally) that are working on cellular therapeutics. As the UK is one of the leading investigators of stem cell research, this will enhance the competitiveness cell therapy groups within the UK for the translation of cellular therapies to the clinic. The advances in physical sciences, life sciences and imaging methodologies have the potential for impact within their own specific disciplines and can be utilized for numerous applications and will be disseminated through the most appropriate channels.

2. Industry: This proposal will potentially impact on a number of industrial sectors. As the commercial cell therapy industry increases nationally and internationally and with the set up of investment schemes such as the "The TSB Catapult" to accelerate translation to the clinic, there will be a significant change for exploitive investigations of stem cell therapies within leading markets and established pharmaceutical industries. Developing techniques that can provide a predictive measurement of tumour delivery with therapeutic outcome are also of great interest to pharmaceutical companies. Lastly, product companies such as novel imaging/devices companies and contrast agent development companies that specialize in biofuntionalisation of nanoparticles for diagnosis, will also be beneficiaries.

3. Third sector: The charitable investment in regenerative medicine at present reflects the funding for an emerging technology. It is therefore anticipated that charitable funding will increase significantly. With those such as namely concerned with stems cells therapies but also in this case lung cancer charities such as The British Lung Foundation will also benefit.

4. The Public: Mesenchymal stem cells (MSCs) have the potential to benefit to a vast number of diseases, with the potential to change the outcomes of diseases that affect the general well being an entire population. The technologies that we propose to develop in our MSCs are transferable to other models of regenerative disease and other cellular therapies such as T cells. Therefore the advances made by this proposal will be utilized to assess the efficacy of cell therapies and the longevity of their potential treatments that when translated will aid the NHS in patient therapy planning and highlight potential risks. We also recognize that discoveries concerning stem cells attract intense media interest. Therefore, we will utilizing both UCL and specific charities such as those mentioned above to engage with public specific engagement mechanisms such as the Regenerative Medicine Network.