Differentiation of GMP-grade human embryonic stem cells to midbrain dopaminergic neurons for transplantation

GMP级人胚胎干细胞分化为中脑多巴胺能神经元用于移植

• 批准号: MR/K017276/1
• 负责人: Tilo Kunath
• 金额: $ 60.62万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK017276%2F1
• 关键词: Differentiation; GMP; grade; human; embryonic

Parkinson's disease (PD) is an incurable and progressively degenerative condition. Although the symptoms are well managed at the early stages with medication, there is currently no treatment to halt or reverse the progress of PD. In the late 1980s and 1990s several PD patients received transplants of fetal midbrain tissue containing dopamine-producing neurons. A small fraction of patients showed tremendous benefit from such grafts. A multi-centre European clinical trial led by co-applicant Dr. Roger Barker, TRANSEURO, is underway to re-visit fetal midbrain transplants and systematically address all potential problems faced in the earlier clinical trials. These trials will be small due to the limiting amount of fetal tissue available. There will be a pressing need to resolve the critical issues of scaleable supply and quality of appropriate dopaminergic neurons for any future widespread use in the treatment of PD. Replacing fetal midbrain tissue with dopaminergic neurons differentiated from human embryonic stem cells (hESCs) is the most realistic solution to this cell source problem. Currently 5 different centres in the UK (Edinburgh, London, Manchester, Newcastle, and Sheffield) have established clinical-grade hESC lines, over 15 lines in total. This proposal will examine all UK clinical-grade hESC lines and compare them for their ability to make dopaminergic neurons. We will modify and optimise a novel method to transform hESCs to dopaminergic neurons from our collaborator Dr. Lorenz Studer (Sloan-Kettering, NYC). The best performing hESC line will be used for transplantation into two distinct rat models of PD. Graft survival, behavioural improvements, and absence of tumour formation will all be carefully assessed. The success of this project using hESC-derived dopaminergic neurons in pre-clinical rat models of PD will be a significant step towards the first-in-human clinical trials.

帕金森病（PD）是一种无法治愈的渐进性退行性疾病。虽然这些症状在早期阶段通过药物治疗得到了很好的控制，但目前还没有治疗方法可以阻止或逆转PD的进展。在20世纪80年代末和90年代，一些帕金森病患者接受了含有多巴胺产生神经元的胎儿中脑组织移植。一小部分患者从这种移植物中获得了巨大的益处。由共同申请人TRANSEURO的Roger Barker博士领导的多中心欧洲临床试验正在进行中，以重新访问胎儿中脑移植并系统地解决早期临床试验中面临的所有潜在问题。由于可用的胎儿组织数量有限，这些试验规模较小。将有一个迫切需要解决的关键问题，可扩展的供应和质量适当的多巴胺能神经元的任何未来广泛使用的治疗PD。用从人胚胎干细胞（hESC）分化的多巴胺能神经元替代胎儿中脑组织是解决这一细胞来源问题的最现实的解决方案。目前，英国有5个不同的中心（爱丁堡、伦敦、曼彻斯特、纽卡斯尔和谢菲尔德）已经建立了临床级hESC细胞系，总共超过15个细胞系。该提案将检查所有英国临床级hESC系，并比较它们制造多巴胺能神经元的能力。我们将修改和优化我们的合作者Lorenz Studer博士（Sloan-Kettering，NYC）将hESC转化为多巴胺能神经元的新方法。表现最好的hESC系将用于移植到两种不同的PD大鼠模型中。移植物存活率、行为改善和无肿瘤形成都将进行仔细评估。在PD的临床前大鼠模型中使用hESC衍生的多巴胺能神经元的该项目的成功将是迈向首次人体临床试验的重要一步。

项目成果

Derivation of the clinical grade human embryonic stem cell line RCe015-A (RC-11).

临床级人胚胎干细胞系 RCe015-A (RC-11) 的衍生。

• DOI: 10.1016/j.scr.2016.04.021
• 发表时间: 2016
• 期刊: Stem cell research
• 影响因子: 1.2
• 作者: De Sousa PA

Synaptic signalling in a network of dopamine neurons: what prevents proper intercellular crosstalk?

• DOI: 10.1002/1873-3468.13910
• 发表时间: 2020-08-30
• 期刊: FEBS LETTERS
• 影响因子: 3.5
• 作者: Chen，Yixi;Kunath，Tilo;Sylantyev，Sergiy
• 通讯作者: Sylantyev，Sergiy

Cryopreservation of Human Midbrain Dopaminergic Neural Progenitor Cells Poised for Neuronal Differentiation.

• DOI: 10.3389/fcell.2020.578907
• 发表时间: 2020
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Drummond NJ;Singh Dolt K;Canham MA;Kilbride P;Morris GJ;Kunath T
• 通讯作者: Kunath T

The Molecular Karyotype of 25 Clinical-Grade Human Embryonic Stem Cell Lines.

• DOI: 10.1038/srep17258
• 发表时间: 2015-11-26
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Canham MA;Van Deusen A;Brison DR;De Sousa PA;Downie J;Devito L;Hewitt ZA;Ilic D;Kimber SJ;Moore HD;Murray H;Kunath T
• 通讯作者: Kunath T