Human blood-derived endothelial colony forming cells as a new cell therapy for chronic non-healing wounds

Chronic non-healing wounds are considered a silent and expensive epidemic. In the UK, the NHS treated 2.2 million adult patients with wounds in 2012 alone at a cost of £5.0 billion. In addition, chronic wounds such as diabetic ulcers are difficult to heal and this is burdensome to patients. Therefore, there is an unmet clinical need for new therapies to improve healing rates. This project will use regenerative medicine approaches to improve healing of wounds.

80-90% of leg ulcers are caused by vascular disease, and new blood vessel formation is considered a key factor for effective wound healing. Hence, we propose a vascular stem cell therapy for chronic wounds: using cells called endothelial colony forming cells (ECFCs) isolated from human blood. We and others have demonstrated that ECFCs are a subtype of endothelial progenitor with the most therapeutic potential for blood vessel regeneration. ECFCs injected directly into diseased tissues such as the limb and retina have potential to repair blood vessels and reverse tissue damage. This project is a feasibility study to demonstrate that ECFCs have a therapeutic role in diabetic wounds. To further develop ECFCs as a viable cell therapy, we will develop a Potency Assay to test the efficiency of ECFCs to perform. This is important to establish a quality assurance and to meet regulatory requirements.

Chronic non-healing wounds are a major socioeconomic burden worldwide and remain a therapeutic challenge. Some cell therapies based on MSCs and BM-MNCs are being tested to accelerate the wound healing process. A critical factor to achieve wound closure is effective angiogenesis and the majority of chronic wounds, including diabetic ulcers, exhibit impaired neovascularisation. Therefore, we propose a cell therapy based on vasoreparative endothelial progenitor cells known as endothelial colony forming cells (ECFCs) to promote vascular repair that will facilitate wound healing. Our published evidence demonstrates that ECFCs are a highly pure subpopulation of endothelial progenitors isolated from human blood and defined as CD31+CD105+CD14-CD45- cells with clonogenic potential and unequivocal endothelial phenotype. ECFCs contribute directly to angiogenesis by de novo vessel formation and by direct incorporation into pre-existing capillaries. Importantly, we have shown that ECFCs contribute to vascular repair in ischaemic tissues using mouse models for hind limb and retinal ischaemia. This project will harness the vasoreparative properties of ECFCs as a new therapy for chronic wounds. We will use a well-established and clinically-relevant model of diabetic wounds i.e. the mouse silicone-splinted excisional wound model to demonstrate feasibility and efficacy of ECFCs in diabetic wounds. In addition, we will validate a 3D Matrigel-based in vitro tube formation assay as a potency assay for quality control of ECFCs when considered a cell therapy product. This is a legal requirement for ATMPs to ensure consistency in the performance of cells as therapeutics.

Who might benefit from this research?
We have identified the following non-academic stakeholders:
*Industry
*University Research and Enterprise
*Schools
*Diabetic Patients
*Policymakers (MPs)

How might they benefit from this research?
To deliver impact, we have the following goals:

1. TO OPTIMISE VASCULAR STEM CELL THERAPIES. The pre-clinical data to be generated by this research project will not only demonstrate feasibility of a cord blood-derived ECFC therapy for chronic ulcers, but will importantly increase interest and investment by the Regenerative Medicine Industry into Cell Therapies for blood vessel regeneration. Positive results have implications for other diseases besides diabetic ulcers, since therapeutic angiogenesis is also needed in myocardial infarction, critical limb ischaemic, and stroke.

2. TO ACCELERATE THE DEVELOPMENT AND IMPLEMENTATION OF NEW CELL THERAPIES FOR DIABETIC VASCULAR COMPLICATIONS. Our ultimate goal is to translate our basic research findings into novel treatments for the benefit of diabetic patients. Data from this project will serve as an important foundation to facilitate the development of a GMP-cell therapy product. We expect to use evidence generated in this study for official meetings with the MHRA/EMA to discuss milestones needed in relation to meet regulatory compliances to develop an ATMP.

3. TO DEVELOP A CELL THERAPY INDUSTRY IN NORTHERN IRELAND. Although various Research Groups at Queen's University Belfast are making important discoveries in the Regenerative Medicine arena, this basic science is not effectively being translated into the clinics. One of the reasons is the lack of Cell Therapy Industry in Northern Ireland, for example, we do not have a GMP-Cell Therapy Manufacturing Facility. Therefore, for the GMP-prototype we are collaborating with the Edinburgh GMP manufacturing facility for Tissues, Cells, and Advanced Therapeutics led by Prof Mark Turner and Prof John Campbell. There is potential to create a spin out company in Regenerative Medicine in Northern Ireland based on the cell therapy product, GMP manufacture, or related technologies.

4. TO EDUCATE POLICYMAKERS AND THE PUBLIC ABOUT THE IMPORTANCE OF SCIENTIFIC RESEARCH IN DIABETES. Our team is committed to education through public engagement. We are involved in international, national, and local events in relation to diabetes research. Data from this project will be useful to showcase meaningful diabetes research in events such as Diabetes Discovery Day (JDRF), Diabetes patient groups (Diabetes UK and Type-2 Action NI), and Northern Ireland Science Festival (Department for the Economy and Innovate UK).