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

通过移植胎儿腹侧中脑替代多巴胺(DA)神经元是治疗帕金森病(PD)的一种潜在的恢复性治疗方法。胚胎干细胞是一种可行的替代胎儿细胞的细胞替代疗法，因为它们是可再生的，可以控制细胞类型的特异性和体外处理的重复性。我们已经从灵长类和人类ES细胞来源中获得了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。慢性全身输液建立的MPTP灵长类动物模型是目前可用于PD和L-多巴模型的最佳功能模型 相关并发症。这些接受MPTP治疗的灵长类动物出现了人类疾病的特征运动体征，在模型中，L-多巴也改善了这种体征。在帕金森病患者中，重复服用L-多巴可引起异常的不自主运动；L-多巴可引起运动障碍。首先，我们将检测移植的来源于人类ES细胞的有丝分裂后DA神经元改善MPTP灵长类动物PD征象的能力，并与标准的L-多巴疗法进行比较。详细的运动行为评估、使用PET特异性DA放射性示踪剂的功能神经成像和功能MRI将确定移植的DA神经元的功能效果。然后将这些数据与移植细胞组成、宿主反应和连接性的尸检分析结合起来进行分析。目的2，确定来自灵长类ES细胞(不需要免疫抑制)的移植DA表型对运动障碍的影响。L多巴反复给药对MPTP PD模型灵长类动物运动障碍的影响 并在移植前后进行系统评分。在这类动物中还将进行功能成像研究，以检查ES来源的DA神经元的成熟和功能整合到宿主电路中。通过在神经组织学核心中对移植的帕金森病患者(带有人胎儿DA神经元)进行相应的临床和组织学研究，进一步分析了所产生的数据、结论和假设以及数据。本项目中以帕金森病为中心的工作是必要的，以确定人和灵长类动物ES细胞来源的DA神经元在帕金森病灵长类模型中的生长、功能益处和安全性，以便潜在地将实验假说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.