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

帕金森氏病(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来阻止或逆转帕金森病的进展。在20世纪80年代末和90年代，几名帕金森氏症患者接受了含有多巴胺产生神经元的胎儿中脑组织的移植。一小部分患者从这种移植物中显示出巨大的好处。一项由联合申请者、特兰苏罗的罗杰·巴克博士领导的多中心欧洲临床试验正在进行中，以重新检查胎儿中脑移植，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，这些试验将是小规模的。迫切需要解决可扩展的适当多巴胺能神经元的供应和质量的关键问题，以便将来在帕金森病的治疗中广泛使用。用人胚胎干细胞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方法。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)建立了临床级hESC系列，总共超过15条系列。这项建议将检查所有英国临床级hESC株，并比较它们制造多巴胺能神经元的能力。我们将修改和优化一种新的方法，将hESCs转化为多巴胺能神经元，该方法来自我们的合作者Lorenz Studer博士(纽约斯隆-凯特琳)。表现最好的hESC将用于移植到两种不同的帕金森病大鼠模型中。移植物存活率、行为改善和无肿瘤形成都将被仔细评估。在帕金森病临床前大鼠模型中使用hESC来源的多巴胺能神经元的这一项目的成功，将是迈向人类临床试验的重要一步。

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.