Development of CM-CS1 CAR Treg to Treat Amyotrophic Lateral Sclerosis (ALS)

开发 CM-CS1 CAR Treg 治疗肌萎缩侧索硬化症 (ALS)

基本信息

批准号：
10696512
负责人：
Joana M Murad
金额：
$ 46.7万
依托单位：
CELDARA MEDICAL, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10696512
关键词：
ALS patients Affect Age Years Age of Onset Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Anti-Inflammatory Agents Antigens Attenuated Binding Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor Breeding CD4 Positive T Lymphocytes Cell Therapy Cell physiology Cells Clinic Clinical Communities Cytoplasmic Protein Data Development Diagnosis Disease Disease Progression Disease model Engineering Engraftment Exclusion Genetic Engineering Goals Heredity Homeostasis Human Immune Incidence Individual Inflammation Injections Interleukin-10 Life Limb structure Macrophage Mediating Microglia Modeling Motor Neurons Mus Muscular Atrophy Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Oncology Oxidative Stress Paralysed Parkinson Disease Pathogenesis Patients Phase Play Progressive Disease Proteins Regulatory T-Lymphocyte Reporting Risk Role Route Sampling Site Spinal Cord T-Lymphocyte Therapeutic Therapeutic Intervention Tissues Toxicology Transgenes United States autoinflammatory chimeric antigen receptor design effector T cell engineered T cells extracellular familial amyotrophic lateral sclerosis glial activation in vivo innovation manufacture motor neuron degeneration mouse model mutant nervous system disorder neuroinflammation neuron loss neuronal survival neuroprotection novel prevent protein aggregation superoxide dismutase 1 therapeutic target therapeutically effective translational therapeutics

项目摘要

SUMMARY Amyotrophic lateral sclerosis (ALS) patients develop fatal paralysis as a result of progressive motor neuron loss in the brain and spinal cord. There are more than 5,000 new cases of ALS per year in the United States, with typical age of onset between 40 and 70 years of age. While SOD1 is a cytoplasmic protein, misfolded SOD1 can be secreted and form extracellular oligomers and aggregates. Mutations in superoxide dismutase-1 (mSOD1) result in misfolding and aggregation of SOD1 and are found in a subset of familial ALS cases. However, misfolded SOD1 has also been identified in spinal cord samples from many sporadic cases of ALS. Regulatory T cells (Tregs) have tolerogenic and anti-inflammatory functions and are being pursued as cell-based therapeutics to block auto-inflammatory immune cells. Higher numbers of Tregs (CD4+CD25hiCD127lo) in ALS patients are associated with a slower disease progression. We have developed novel chimeric antigen receptors (CARs) that recognize aggregated SOD1 and trigger Treg function. In this manner, we aim to provide a large number of Tregs that are specific for a disease-associated protein and will become activated at the site of misfolded, aggregated SOD1. We have further enhanced the activity of CAR Tregs by engineering them to produce BNDF, a key neuronal survival factor. We have developed a novel mouse model for ALS by breeding the G93A SOD1 transgene onto the NSG mouse background to create mSOD1-NSG mice. These mice allow the engraftment of human cells and they develop a progressive disease resulting in inflammation in the spinal cord and limb paralysis that mimic findings in ALS. The aim of this project is to perform IND-enabling studies required for translation of this therapy into the clinic.

概括肌萎缩性侧索硬化症（ALS）患者由于进行性运动神经元丧失而出现致命瘫痪在大脑和脊髓中。美国每年有5,000多个新案件，其中典型的发病年龄在40至70岁之间。虽然SOD1是一种细胞质蛋白，但错误折叠的SOD1可以分泌并形成细胞外的低聚物和聚集体。超氧化物歧化酶1（MSOD1）中的突变导致SOD1的错误折叠和聚集，并在家族性ALS病例的一部分中发现。然而，在许多零星病例的脊髓样品中也发现了错误折叠的SOD1。监管 T细胞（Tregs）具有耐受性和抗炎功能，并作为基于细胞的作用。疗法可阻止自炎性免疫细胞。 ALS中较高数量的Treg（CD4+CD25HICD127LO）患者与疾病进展较慢有关。我们已经开发了新型的嵌合抗原受体（汽车）识别聚合的SOD1并触发Treg函数。通过这种方式，我们旨在提供大型针对疾病相关的蛋白质特异的Treg数量，并将在错误折叠的，聚合的SOD1。我们通过工程来进一步增强了汽车Treg的活动产生BNDF，这是关键的神经元存活因子。我们通过繁殖开发了一种新型的ALS鼠标模型 G93A SOD1转基因在NSG鼠标背景上创建MSOD1-NSG小鼠。这些老鼠允许人类细胞的植入，它们发展出一种进行性疾病，导致脊柱发炎绳索和肢体瘫痪，模仿ALS中的发现。该项目的目的是进行辅助研究将这种疗法转化为诊所所需的。