Transplantation of ES Cell-derived DA Neurons into PD Primate Models

通过移植胎儿腹侧中脑来替代多巴胺（DA）神经元是帕金森病（PD）的一种潜在恢复疗法。胚胎干细胞（ES）是用于基于细胞的替代疗法的胎儿细胞的现实替代物，因为它们是可再生的，可以控制细胞类型特异性和体外处理的再现性。我们已经从灵长类动物和人类ES细胞来源获得DA神经元。在这个项目中，我们将通过移植到MPTP PD灵长类动物模型中来确定来自人ES细胞的未成熟有丝分裂后DA神经元的治疗潜力。通过慢性全身输注产生的MPTP灵长类动物模型是目前PD和L-DOPA的最佳可用功能模型 相关并发症。这些MPTP治疗的灵长类动物发展出人类疾病的特征性运动体征，在模型中也用L-DOPA改善。如在PD患者中所见，重复给予L-DOPA诱导异常不自主运动; L-DOPA诱导运动障碍。首先，我们将研究移植的有丝分裂后DA神经元来源于人类ES细胞，以改善MPTP灵长类动物的PD体征的能力，与标准的左旋多巴治疗相比。详细的运动行为评价、使用PET特异性DA放射性示踪剂的功能性神经成像和功能性MRI将确定移植的DA神经元的功能效应。然后结合移植细胞组成、宿主反应和连接性的尸检分析来分析这些数据。目的2，确定来自灵长类ES细胞的DA表型（不需要免疫抑制）移植对运动障碍的影响。在稳定的MPTP PD模型灵长类动物中通过重复给予L-DOPA诱导运动障碍 然后在移植前后进行系统评定。还将在这些动物中进行功能成像研究，以检查ES衍生的DA神经元成熟和功能整合到宿主电路中。通过解决在神经组织学核心中进行的移植PD患者（具有人胎儿DA神经元）的相应临床和组织学研究，进一步分析生成的数据、结论和假设以及数据。本项目中的PD重点工作对于确定人类和灵长类ES细胞衍生的DA神经元在灵长类PD模型中的生长、功能益处和安全性是必要的，以便将实验假设潜在地转化为临床有效和安全的程序。

The replacement of dopamine (DA) neurons by transplanting fetal ventral midbrain is a potential restorative therapy for Parkinson's disease (PD). Embryonic stem (ES) cells are a realistic alternative to fetal cells for cell-based replacement therapies since they are renewable, can be controlled for cell type specificity and reproducibility of in vitro processing. We have derived DA neurons from primate and human ES cell sources. In this project we will determine the therapeutic potential of immature post-mitotic DA neurons derived from human ES cells by transplantation into a MPTP PD primate model. The MPTP primate model produced by chronic systemic infusions is currently the best available functional model for PD and L-DOPA related complications. These MPTP-treated primates develop the characteristic motor signs of the human disease, that also improve with L-DOPA in the model. As seen in PD patients, repeated L-DOPA administration induces abnormal involuntary movements; the L-DOPA induced dyskinesias. First, we will examine the capacity of transplanted post-mitotic DA neurons derived from human ES cells to improve PD signs in MPTP primates, in comparison to standard L-DOPA therapy. Detailed motor behavioral evaluation, functional neuroimaging using PET specific DA radiotracers and functional MRI will determine the functional effects of the transplanted DA neurons. Such data is then analyzed in conjunction with post mortem analyses of transplant cell composition, host reactions and connectivity. Aim 2, determines the effects of the transplanted DA phenotype derived from primate ES cells (not requiring immune suppression) on dyskinesias. Dyskinesias are induced by repeated L-DOPA administration in stable MPTP PD model primates and then rated systematically before and after transplantation. Functional imaging studies in such animals will also be performed to examine maturation and functional integration of ES derived DA neurons into the host circuitry. The data, conclusion and hypotheses generated and data are analyzed further by addressing the corresponding the clinical and histological studies of transplanted PD patients (with human fetal DA neurons) performed in the neurohistology core. The PD focused work in this project is necessary to determine the growth, functional benefits and safety of human and primate ES cell derived DA neurons in a primate model of PD, in order to potentially translate the experimental hypothesis into clinically effective and safe procedures.