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.

肌萎缩侧索硬化症 (ALS) 中致命性瘫痪的发生是由进行性的 中枢神经系统（CNS）运动神经元退化。抑制持久性和毒性 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学策略 防止疾病进展。传统的抗炎药物对中枢神经系统的活性有限，尚未被广泛应用。 迄今为止对 ALS 有效。调节性 T 细胞 (Treg) 是淋巴细胞的一个子集，具有固有的抗炎作用 活性，能够渗透到中枢神经系统，并且大量的 Tregs 与较慢的速度相关。 ALS 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 运用多种机制来治疗 ALS，使用基因增强的 Tregs 来提供多种治疗活性。 我们将使用两类编码我们所说的神经退行性疾病的治疗基因 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 T 细胞疗法是一种提供额外治疗活性的方法 患病部位的中枢神经系统。我们将测试分泌的神经元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以下假设：NDMM 表达 Tregs 将增强治疗效果并防止 ALS 模型中神经元死亡。这项概念验证研究将允许探索其他 NDMM 类分子来调节额外的神经元存活或 免疫调节途径。治疗性 CAR Tregs 的潜在治疗突破将带来 对患者、其家庭以及 ALS 的临床管理产生重大影响。