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.

概括肌萎缩侧索硬化症 (ALS) 患者因进行性运动神经元丧失而出现致命性瘫痪在大脑和脊髓中。美国每年新增 5,000 多例 ALS 病例，其中典型发病年龄在40岁至70岁之间。虽然 SOD1 是一种细胞质蛋白，但错误折叠的 SOD1 可以被分泌并形成细胞外寡聚物和聚集体。超氧化物歧化酶 1 (mSOD1) 突变导致 SOD1 错误折叠和聚集，并在部分家族性 ALS 病例中发现。然而，在许多散发性 ALS 病例的脊髓样本中也发现了错误折叠的 SOD1。监管 T 细胞 (Treg) 具有致耐受性和抗炎功能，作为基于细胞的 T 细胞正在被研究阻断自身炎症免疫细胞的疗法。 ALS 中的 Tregs (CD4+CD25hiCD127lo) 数量较多患者的疾病进展较慢。我们开发了新型嵌合抗原受体（CAR）识别聚合的 SOD1 并触发 Treg 功能。通过这种方式，我们的目标是提供大量特定于疾病相关蛋白的 Tregs 数量，将在该蛋白的位点被激活错误折叠、聚集的 SOD1。我们进一步增强了 CAR Tregs 的活性，将其改造为产生 BNDF，一种关键的神经元生存因子。我们通过育种开发了一种新型 ALS 小鼠模型将 G93A SOD1 转基因转移到 NSG 小鼠背景上以创建 mSOD1-NSG 小鼠。这些小鼠允许人类细胞的植入，它们会发展成一种进行性疾病，导致脊柱炎症脊髓和肢体麻痹类似于 ALS 的表现。该项目的目的是进行 IND 支持研究将这种疗法转化为临床所需的。