Individualized Cell Therapy for Parkinson's Disease

描述（由申请人提供）：帕金森病（PD）由中脑多巴胺（DA）神经元变性引起，在初始阶段可用左旋多巴有效治疗。然而，DA补充剂并不能阻止DA神经元的变性过程，也不能纠正DA神经元的丢失。因此，随着时间的推移，PD患者几乎总是失去对左旋多巴治疗的反应性。移植人胚胎中脑组织以替代丢失的DA神经元已显示出缓解一些PD患者症状的功效。然而，这种疗法依赖于从单个患者的特定年龄的多个胎儿收集组织，这使得它对于一般应用是不切实际的，并且在伦理上是有问题的。该提案探讨了未来使用非人灵长类动物模型进行PD个性化细胞治疗的可能性。我们将通过产生无病毒和转基因的诱导多能干细胞（iPSC），并使用我们新开发的中脑DA神经元分化策略，从帕金森病恒河猴个体的皮肤组织中获得安全和功能性DA神经元。然后，我们将对细胞进行遗传标记，并将中脑DA神经元移植回细胞来源的猴子，并评估DA神经元是否存活并在短期内有助于治疗，以及治疗结果是否长期持续（2-3年）。这项研究的结果将确定自体干细胞治疗灵长类动物PD的安全性和有效性，从而为未来使用重编程人类细胞进行临床试验奠定基础。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) results from degeneration of midbrain dopamine (DA) neurons and can be effectively treated with L-dopa in the initial phase. However, DA supplementation does not halt the DA neuron degeneration process, nor does it correct the loss of DA neurons. Consequently, PD patients almost invariably lose responsiveness to L-dopa treatment over time. Transplantation of human fetal mesencephalic tissues to replace the lost DA neurons has shown efficacy in alleviating symptoms of some PD patients. This therapy, however, depends on collection of tissues from multiple fetuses of particular ages for a single patient, which makes it impractical for general application and is ethically problematic. This proposal explores the possibility of future personalized cell therapy for PD using a non-human primate model. We will derive safe and functional DA neurons from the skin tissue of individual Parkinsonian rhesus monkeys through generation of induced pluripotent stem cells (iPSCs) that are free of virus and transgenes and using our newly developed strategy for midbrain DA neuron differentiation. We will then label the cell genetically and transplant the midbrain DA neurons back to the monkey from which the cells are derived, and assess whether the DA neurons survive and contribute to therapy in a short term and whether the therapeutic outcome is sustained over a long term (2-3 years). Results from this study will determine the safety and efficacy of autologous stem cell therapy for PD in primates, thus setting up a foundation for future clinical trials using reprogrammed human cells.