Individualized Cell Therapy for Parkinson's Disease

描述（申请人提供）：帕金森病（PD）是由中脑多巴胺（DA）神经元退行性变引起的，在初始阶段用左旋多巴可以有效治疗。然而，补充DA并不能阻止DA神经元的退化过程，也不能纠正DA神经元的丢失。因此，随着时间的推移，PD患者几乎总是对左旋多巴治疗失去反应性。移植人胎儿中脑组织替代缺失的DA神经元，可有效缓解部分PD患者的症状。然而，这种疗法依赖于从单个患者的特定年龄的多个胎儿中收集组织，这使得它不适合普遍应用，并且存在伦理问题。该建议探讨了未来使用非人类灵长类动物模型进行PD个性化细胞治疗的可能性。我们将通过诱导多能干细胞（iPSCs）的产生，从个体帕金森恒河猴的皮肤组织中获得安全功能的DA神经元，这种诱导多能干细胞不含病毒和转基因，并使用我们新开发的中脑DA神经元分化策略。然后，我们将对细胞进行遗传标记，并将中脑DA神经元移植回提取细胞的猴子体内，并评估DA神经元是否能在短期内存活并有助于治疗，以及治疗结果是否能在长期（2-3年）内持续。本研究的结果将确定自体干细胞治疗灵长类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.