The Pluripotent Stem Cell Platform (PSCP)

人类多能干细胞(PSC)生物学的进步提供了前所未有的机会，为几乎无限数量的所有人类组织和器官产生安全的供体细胞。利用这些进展将使一系列新的细胞介导疗法成为可能。要实现这些雄心壮志，需要一种翻译结构，将基本发现整合到医疗产品和应用的管道中。多能干细胞平台(PSCP)是这样一个翻译联盟，汇集了谢菲尔德干细胞生物学中心、WT/MRC干细胞研究所、剑桥大学健康合作伙伴、拉夫堡领导的EPSRC再生医学创新制造中心、惠康信托桑格研究所、巴普拉姆研究所和NIBSC，以利用PSC生物学的进展来开发再生医学。PSCP将实施一项翻译研究计划，以实现以下目标：i)PSC的无转基因、符合EUCTD、生产、扩展和安全鉴定的协议；ii)在PSC制造过程中尽量减少功能上重要的基因或表观变异的发生；Iii)标准化的PSC分化方案，用于派生、制造和储存具有治疗意义的特定谱系的中间干细胞；iv)符合法规要求的适用于临床使用的PSC产品的合格工艺。为了实现这些目标，私营部门合作伙伴关系将涉及三个主题。主题1“细胞特性和稳定性”将提供一个平台，用于推导和验证符合EUCTD的IPSC和PSC扩大GMP规模的协议，以及确定质量验收标准，以实现标准化和向自动化平台过渡。它还将提供工具，用于监测PSC的遗传和表观遗传学变化，以及最大限度减少有害变异的培养改进，以及评估这些变异对再生医学构成的潜在风险。主题2“了解分化途径”将提供扩增PSC来源的神经前体细胞的方案，这些神经前体细胞具有稳定的分化为多巴胺能神经元和耳神经细胞的潜力，还将为内胚层前体细胞的产生和扩增提供方案。它将涉及生物学与工艺工程和制造的结合，包括对制造和供应需求的评估，以及确定首选的生产系统和技术配置以及相关的风险评估和缓解战略。主题3“质量控制、安全和再现性”将优化对可能危及安全的外来病原体的检测，并提供参考标准。PSCP将在可行的商业模式下，为我们选择的临床样本确定以可接受的商品成本进行GMP操作的障碍，并通过建立能够在三个地点证明可比性的可扩展制造工艺和测量系统来解决可重复性和可比性的关键问题。PSCP将积极参与与其他组织的网络联系，特别是与Catapult和其他行业合作伙伴，以及与Yamanaka教授和CiRA(日本京都)的网络，这将使IPSC的生产快速启动，并为中心提供最高水平的国际基准。PSCP将组织三个研讨会，讨论制造、安全和标准化以及临床交付技术。研讨会将旨在就与候选细胞疗法有关的制造、风险评估和安全测试的“最佳实践原则”达成共识。PSCP将对生物产业的竞争前研究采用开放式创新模式，目的是与一个行业联盟合作，设计和执行一系列示范项目，重点是干细胞制造中的通用问题，特别是细胞质量、遗传完整性和效力的分析测量。

Advances in human pluripotent stem cells (PSC) biology provide unprecedented opportunities to generate safe donor cells for all human tissues and organs in virtually unlimited numbers. Harnessing these advances will enable an array of novel cell-mediated therapies. Realising these ambitions requires a translational structure that melds fundamental discoveries into a pipeline for medical products and applications. The Pluripotent Stem Cell Platform (PSCP) is such a translational alliance, bringing together the Sheffield Centre for Stem Cell Biology, the WT/MRC Stem Cell Institute, Cambridge University Health Partners, the Loughborough led EPSRC Centre for Innovative Manufacturing in Regenerative Medicine, the Wellcome Trust Sanger Institute, the Babraham Institute and NIBSC, to exploit advances in PSC biology for the development of regenerative medicine.PSCP will implement a translational research programme to reach the following goals: i) protocols for transgene-free, EUCTD-compliant, production, expansion and safety qualification of PSC; ii) methods to minimise occurrence of functionally significant genetic or epigenetic variants during PSC manufacturing; iii) standardised PSC differentiation protocols for deriving, manufacturing and banking therapeutically relevant lineage-specific intermediate stem cells; iv) qualified processes for manufacturing regulatory compliant PSC products suitable for clinical use. To reach these goals the PSCP will address three themes. Theme 1, "Cell characterization and stability", will provide a platform for derivation and validation of EUCTD compliant iPSC and protocols for GMP scale up of PSC, as well as identification of quality acceptance criteria to enable standardisation and transition to automated platforms. It will also provide tools for monitoring genetic and epigenetic changes in PSC and culture refinements that minimize deleterious variants, and an assessment of potential risks posed by these variants for regenerative medicine. Theme 2, "Understanding routes to differentiation", will provide protocols for expansion of PSC-derived neural progenitors with stable potential for differentiation into dopaminergic and otic neurons and also for the generation and expansion of endodermal progenitors. It will address the integration of biology with process engineering and manufacture, including assessment of manufacturing and supply requirements and identification of preferred production system and technology configurations and associated risk assessments and mitigation strategies. Theme 3, "Quality control, safety and reproducibility", will optimise the detection of adventitious agents that may compromise safety, and provide reference standards. It will determine the barriers to operational GMP for our chosen clinical exemplars at acceptable cost of goods within a viable business model and address the key issues of reproducibility and comparability by establishing a scaleable manufacturing process and measurement system capable of allowing demonstration of comparability at three sites.PSCP will actively engage in networking with other groups, notably with the Catapult and other industry partners, and with Prof Yamanaka and CiRA (Kyoto, Japan), which will enable a rapid start in iPSC production and provide the highest level of international bench-marking for the Hub. PSCP will organise three workshops addressing manufacturing, safety and standardisation, and clinical delivery technologies. The workshops will aim to develop a consensus on 'principles of best practice' for manufacturing, risk assessment and safety testing pertaining to the candidate cell therapies. PSCP will adopt an open innovation model for pre-competitive research with bioindustry, with the intent of engaging with an industry consortium to design and execute a set of demonstration projects focused on generic issues in stem cell manufacturing, notably analytical measures of cell quality, genetic integrity and potency.