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

使用神经退行性疾病修饰分子 (NDMM) 的细胞疗法作为调节 ALS 氧化损伤和神经元存活的手段

• 批准号: 10038210
• 负责人: Charles L. Sentman
• 金额: $ 45.1万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038210
• 关键词: ALS patients; Amyotrophic Lateral Sclerosis; Animal Model; Anti-Inflammatory Agents; Autologous; Binding; Blood - brain barrier anatomy; CAR T cell therapy; Cell Therapy; Cells; Clinic; Clinical Management; Development; Disease; Disease Progression; Engineered Gene; Engineering; FOXP3 gene; Familial Amyotrophic Lateral Sclerosis; Foundations; Genes; Goals; Growth Factor; Human; In Vitro; Inflammation; Laboratories; Lymphocyte Subset; Malignant Neoplasms; Mediating; Mediator of activation protein; Microglia; Modeling; Motor; Motor Neuron Disease; Motor Neurons; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Outcome; Oxidative Stress; Paralysed; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Proteins; Regulatory T-Lymphocyte; Research; Rodent; Sampling; Site; Specificity; Spinal Cord; T cell therapy; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Transgenic Mice; Transgenic Organisms; cancer therapy; chimeric antigen receptor; effector T cell; efficacy testing; engineered T cells; experimental study; family management; first-in-human; immunoregulation; improved; in vivo; innovation; motor neuron degeneration; mouse model; mutant; neoplastic cell; neuroinflammation; neuron loss; neuronal growth; neuronal survival; neuroprotection; neurotoxic; oxidative damage; pre-clinical; prevent; superoxide dismutase 1; therapeutic gene

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.

肌萎缩性侧索硬化症（ALS）的致命瘫痪发展是由进行性的 中枢神经系统（CNS）中运动神经元的变性。抑制持久和有毒 运动神经元周围的神经炎症和氧化损伤是一种有前途的药理策略 预防疾病进展。常规的抗炎药具有有限的CNS活性，尚未 迄今为止在ALS上有效。调节性T细胞（Tregs）是具有固有抗炎的淋巴细胞的子集 活性，能够穿透到中枢神经系统中，较高的Treg与较慢有关 ALS患者的疾病进展。在此提案中，我们旨在证明我们可以创建一种治疗方法 使用多种机制使用基因增强的Treg来处理ALS，以提供多种治疗活动。 我们将使用两类的治疗基因，这些基因编码我们称为神经退行性疾病 修饰分子（NDMMS）。这些基因为Treg提供了增强的治疗活性，这项研究是一项 证明基因增强T细胞疗法是一种提供额外治疗活性的方法 疾病部位的中枢神经系统。我们将测试可预防抗氧化损伤的分泌神经元生长因子和蛋白质。这项拟议的研究的目的是测试假设表达NDMM的假设 Tregs将具有增强的治疗作用，并防止ALS模型中神经元死亡。这项概念验证研究将允许探索其他类似NDMM的分子，以调节其他神经元存活或 免疫调节途径。治疗性汽车Tregs的潜在治疗突破将具有 对患者，家人和ALS的临床管理的重大影响。