Cell therapy using neurodegenerative disease modifying molecules (NDMMs) as a means to modulate oxidative damage and neuronal survival in ALS

肌萎缩侧索硬化症(ALS)致死性瘫痪的发生是由进行性 中枢神经系统(CNS)运动神经元变性。抑制顽固而有毒的 运动神经元周围的神经炎症和氧化损伤是一种很有前途的药物治疗策略 防止疾病进展。传统的抗炎药限制了中枢神经系统的活性，并没有 迄今为止在肌萎缩侧索硬化症中有效。调节性T细胞是具有内在抗炎作用的淋巴细胞亚群。 活动，能够穿透到中枢神经系统，树突状细胞的数量越多，速度越慢 肌萎缩侧索硬化症患者的疾病进展。在这项提案中，我们的目标是证明我们可以创造一种治疗方法 采用多种机制使用基因增强的Tregs来治疗ALS，以提供多种治疗活动。 我们将使用两类治疗性基因来编码我们所说的神经退行性疾病 修饰分子(NDMM)。这些基因为Tregs提供了增强的治疗活性，这项研究是 证明基因增强的T细胞疗法是一种提供额外治疗活性的方法 中枢神经系统在发病部位。我们将测试分泌的神经生长因子和防止抗氧化损伤的蛋白质。这项研究的目的是检验NDMM表达的假设 Tregs将增强ALS模型的治疗效果，防止神经元死亡。这项概念验证研究将允许探索其他类似NDMM的分子来调节额外的神经元存活或 免疫调节途径。治疗汽车Tregs的潜在治疗突破将具有 对肌萎缩侧索硬化症患者及其家属和临床治疗的重大影响。

The development of fatal paralysis in amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons in the central nervous system (CNS). Inhibiting the persistent and toxic neuroinflammation and oxidative damage around motor neurons is a promising pharmacological strategy to prevent disease progression. Conventional anti-inflammatory drugs have limited CNS activity and have not been effective in ALS to date. Regulatory T cells (Tregs) are a subset of lymphocytes with inherent anti-inflammatory activity, are capable of penetration into the CNS, and higher numbers of Tregs are associated with slower disease progression in ALS patients. In this proposal, we aim to demonstrate that we can create a treatment that engages multiple mechanisms to treat ALS using gene-enhanced Tregs to deliver multiple therapeutic activities. We will use two classes of therapeutic genes that encode what we refer to as neurodegenerative disease modifying molecules (NDMMs). These genes provide enhanced therapeutic activity to Tregs, and this study is a way to demonstrate that gene-enhanced T cell therapy is a way to provide additional therapeutic activity in the CNS at the site of disease. We will test both secreted neuronal growth factors and proteins that prevent anti-oxidative damage. The objective of this proposed research is to test the hypothesize that NDMM-expressing Tregs will have enhanced therapeutic effects and prevent the death of neurons in ALS models. This proof-of-concept study will allow other NDMM-like molecules to be explored to modulate additional neuron survival or immunomodulatory pathways. A potential therapeutic breakthrough with therapeutic CAR Tregs would have a major impact on patients, their families, and clinical management of ALS.