Individualized Cell Therapy for Parkinson's Disease

描述(申请人提供)：帕金森病(PD)是中脑多巴胺(DA)神经元变性的结果，早期使用L-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，帕金森病患者几乎总是对L-多巴治疗失去反应性。移植人胎中脑组织替代丢失的DA神经元已显示出缓解部分帕金森病患者症状的效果。然而，这种疗法依赖于为单个患者收集特定年龄的多个胎儿的组织，这使得它在一般情况下应用不切实际，而且在伦理上存在问题。这项建议探索了未来使用非人类灵长类动物模型对帕金森病进行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(IPSCs)，并使用我们新开发的中脑DA神经元分化策略，从帕金森病猕猴个体的皮肤组织中获得安全和功能良好的DA神经元。然后，我们将对细胞进行基因标记，并将中脑DA神经元移植回细胞来源的猴子，并评估DA神经元是否在短期内存活并有助于治疗，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帕金森病的安全性和有效性，从而为未来使用重新编程的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.