Manufacture scale up of human pericyte progenitor cells for regenerative medicine

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Regenerative stem cell therapy offers new hope for treating cardiovascular disease. The potential of this approach is immense but not completely developed. Clinical trials of cell therapy in patients with myocardial infarction (MI) have so far investigated a relatively small number of options, focusing mainly on the use of blood and bone marrow-derived cells. A host of other cells merit attention as they may offer a specialised means for myocardial and vascular reconstitution. Among these, vascular mural cells and pericytes are gaining attention. The rationale of pericyte-based therapy is to stabilise peri-infarct blood vessels, which would remain otherwise prone to leak and break. We have developed a method for easy isolation and expansion of pericytes from human saphenous veins of patients with coronary artery disease. The vein is obtained without harm to the patient using the leftover from coronary artery bypass surgery. Likewise, a small piece of vein could be obtained through minimal invasive surgery to isolate and expand pericytes in culture and obtain million cells ready for clinical use. We demonstrated that transplantation of human pericytes exerts long-term therapeutic benefit in models of limb ischaemia and MI. Noteworthy, pericytes engraft in peri-infarct vascularisation and exert a spectrum of reparative actions, including attraction of resident cardiac stem cells and circulating angiogenic cells. Furthermore, pericytes improve the survival of cardiac cells thus leading to reduction of the infarct size. No safety concerns were reported. The current isolation/expansion method was developed in a common tissue culture laboratory. Hence, we now need to upgrade it to the standards required for clinical use in patients. The present study aims to develop a clinical grade cell product through a series of regulated procedures and quality controls in preparation of a first-in-man clinical study with autologous pericytes in coronary artery disease patients unresponsive to medications and not amenable to revascularization. The term autologous means that pericytes are extracted from the patient vein, expanded and reintroduced into the patient's heart. Use of patient's own cells avoids their rejection and transmission of infectious disease, which are common problems when using cells from a different donor. The project comprises 3 work-packages (WP), 6 milestones (M) and a contingency plan for prevention, troubleshooting and alternative solutions. The goal of WP1 is to scale up current protocol to improve the yield of cells available for clinical use. The goal of WP2 is to transfer the protocol to the facilities of the National Health Service-Blood and Transplant (NHSBT) for clinical-grade manufacture of at least 6 cell lines. This will be followed by quality control of cell stability. The goal of WP3 is to test the performance of the cell product using in vitro functional assays and models of MI. The project will lead to the clinical manufacture of a novel regenerative medicine cell product through the liaison of the University of Bristol and NHSBT, which is the recommended channel for clinical application of autologous cell therapy in UK. Hence, successful completion of proposed work will make the cell product available immediately to the healthcare system for patient benefit.