Manufacture scale up of human pericyte progenitor cells for regenerative medicine

用于再生医学的人类周细胞祖细胞的生产规模扩大

• 批准号: MR/J015350/1
• 负责人: Paolo Madeddu
• 金额: $ 94.4万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ015350%2F1
• 关键词: Manufacture; scale; up; human; pericyte

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.

再生干细胞治疗为心血管疾病的治疗提供了新的希望。这种方法的潜力是巨大的，但尚未完全开发。迄今为止，心肌梗死（MI）患者细胞治疗的临床试验研究了相对较少的选择，主要集中在血液和骨髓来源的细胞的使用。许多其他细胞值得关注，因为它们可能为心肌和血管重建提供专门的手段。其中，血管壁细胞和周细胞越来越受到关注。基于周细胞的治疗的基本原理是稳定梗死周围的血管，否则这些血管将仍然容易渗漏和破裂。我们建立了一种从冠心病患者隐静脉中分离和扩增周细胞的方法。使用冠状动脉搭桥手术的剩余物获得静脉，不会对患者造成伤害。同样，可以通过微创手术获得一小片静脉，以分离和扩增培养中的周细胞，并获得准备用于临床使用的数百万个细胞。我们证明了人周细胞移植在肢体缺血和MI模型中发挥长期治疗益处。值得注意的是，周细胞在梗死周围血管形成中植入并发挥一系列修复作用，包括吸引驻留的心脏干细胞和循环血管生成细胞。此外，周细胞改善心脏细胞的存活，从而导致梗死面积的减小。未报告安全性问题。目前的分离/扩增方法是在普通组织培养实验室中开发的。因此，我们现在需要将其升级到临床使用所需的标准。本研究旨在通过一系列规范程序和质量控制开发临床级细胞产品，以准备在对药物无反应且不适合血运重建的冠状动脉疾病患者中进行自体周细胞的首次人体临床研究。术语自体是指从患者静脉中提取周细胞，扩增并重新引入患者心脏。使用患者自己的细胞可以避免排斥反应和传染病的传播，这是使用来自不同供体的细胞时常见的问题。该项目包括3个工作包（WP）、6个里程碑（M）和一个预防、故障排除和替代解决方案的应急计划。WP 1的目标是扩大目前的方案，以提高可用于临床使用的细胞产量。WP 2的目标是将方案转移至国家卫生服务-血液和移植（NHSBT）机构，用于临床级生产至少6种细胞系。随后将对细胞稳定性进行质量控制。WP 3的目的是使用体外功能试验和MI模型检测细胞产品的性能。该项目将通过布里斯托大学和NHSBT的联络，导致一种新型再生医学细胞产品的临床生产，这是英国自体细胞治疗临床应用的推荐渠道。因此，成功完成拟议的工作将使细胞产品立即可用于医疗保健系统，以造福患者。

项目成果

289Pharmacologic rejuvenation of senescent human cardiac stem cells enhances myocardial repair

289 衰老人心脏干细胞的药理复兴可增强心肌修复

• DOI: 10.1093/cvr/cvu087.3
• 发表时间: 2014
• 期刊: Cardiovascular Research
• 影响因子: 10.8
• 作者: Avolio E

Are racial differences in hospital mortality after coronary artery bypass graft surgery real? A risk-adjusted meta-analysis

• DOI: 10.1016/j.jtcvs.2018.12.002
• 发表时间: 2019-06-01
• 期刊: JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
• 影响因子: 6
• 作者: Benedetto, Umberto;Kamel, Mohamed K.;Gaudino, Mario
• 通讯作者: Gaudino, Mario

P593Human vascular pericytes and cardiac progenitor cells combined transplantation for heart repair

P593人血管周细胞与心脏祖细胞联合移植用于心脏修复

• DOI: 10.1093/cvr/cvu098.23
• 发表时间: 2014
• 期刊: Cardiovascular Research
• 影响因子: 10.8
• 作者: Avolio E