HLA-homozygous iPSC-cardiomyocytE Aggregate manufacturing technoLogies for allogenic cell therapy to the heart (HEAL)

HEAL将专注于诱导多能干细胞疗法的一般瓶颈，特别关注心力衰竭，这仍然是发病率和死亡率的主要原因，治疗选择很少。HLA纯合细胞系衍生的心肌细胞聚集体提供了适用于大患者群体的恢复性心脏治疗的前景，并克服了与自体方法相关的经济障碍。通过开发大规模生产和冷冻保存的解决方案，我们将使同种异体治疗具有最低的免疫抑制要求。免疫原性评估试验将为人工智能算法的开发提供数据，以预测接受者的免疫应答，从而个性化设计免疫抑制方案。将开发一种确保产品有效性的效价试验，以及符合和超过现行法规要求的体外和体内致瘤性试验。将开发一个遗传完整性管道，定义用于严格评估的最敏感的检测方法，并将为治疗的安全工具箱添加一个用于程序性细胞死亡的双等位基因自杀基因形式的救援工具。将在猪模型中确定细胞产物施用在保留和植入方面的优化，包括基于导管的递送作为手术应用的微创替代方案，以及移植物诱导的心律失常的风险评估。通过已建立的联系，与监管机构进行早期对话，将确保按照GMP要求进行适当的开发。通过对欧洲中心的健康技术和基础设施评估，自由运营和许可策略将为批准细胞产品和相关测定以及储存和分销协议奠定基础，这是进行首次基于细胞的心脏修复人体研究所需的。

HEAL will focus on general bottlenecks to induced pluripotent stem cell therapies with a particular focus on heart failure, which remains a major cause of morbidity and mortality with very few treatment options. HLA-homozygous cell line derived cardiomyocyte aggregates offer the prospect of a restorative heart therapy applicable to large patient populations and to overcome economic barriers associated with autologous approaches. By developing solutions for their mass-production and cryopreservation we will enable allogeneic treatment with minimum requirements for immunosuppression. Assays for assessment of immunogenicity will provide data for the development of an artificial intelligence powered algorithm to predict recipients' immune responses for personalised design of immunosuppression protocols. A potency assay to assure product effectiveness will be developed together with assays of tumorigenicity in vitro and in vivo that meet and exceed current regulatory requirements. A genetic integrity pipeline defining the most sensitive assays for rigorous assessment will be developed and a rescue tool in the form of a biallelic suicide gene for programmed cell death will add to the safety toolbox for the therapy. Optimisation of cell-product administration in terms of retention and engraftment, including catheter-based delivery as minimally invasive alternative to surgical application, and assessment of risks of graft-induced arrhythmia will be determined in a pig model. Early dialogues, via established links, to the regulatory authorities will ensure proper development according to GMP requirements. Freedom to operate and licensing strategies with a health technology and infrastructure assessment of European centres will set the scene for approval of the cell product and related assays and protocols for storage and distribution required to progress towards a first in man study of cell-based heart repair.