Creation of CAR-Tregs that are resistant to the senescent environment

创造抵抗衰老环境的 CAR-Tr​​eg

• 批准号: BB/X009610/1
• 负责人: Sian Henson
• 金额: $ 64.96万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX009610%2F1
• 关键词: Creation; CAR; Tregs; resistant; senescent

To date, there is no effective drug to treat the neurodegenerative disease amyotrophic lateral sclerosis (ALS). ALS is a fast-progressing and ultimately fatal condition which leads to selective motor neuron loss and death within two to five years after symptom onset. The current gold standard treatment for ALS is riluzole, a drug without a proven mechanism of action that was developed in the early 1990s. As an unmet need, ALS is a target for drug development. ALS involves abnormalities of the immune system, most strikingly changes to T cells, a specific type of white blood cell. In particular ALS causes the loss of a specialised T cell called a T regulatory cell or Treg. These cells act to dampen down the immune response and maintain self-tolerance, the ability of the immune system to recognise the body as a non-threat and only mount a response to foreign substances. In ALS not only do the numbers of Tregs decline but so also do their potent suppressive ability. Cell therapies are in clinical development and involve expanding patient-derived Tregs but the treatment requires large doses of Tregs and patients decline soon after stopping the infusion. We believe this to be due to the highly pro-inflammatory and pro-senescence (ageing) ALS environment. Reflection Therapeutics have developed a new targeted methodology called a CAR-Treg (CAR, Chimeric Antigen Receptor) that shows improved performance over conventional cell therapies, however, the hostile environment these engineered cells find themselves in needs addressing. Therefore the main aim of this grant is to create a CAR-Treg that specifically targets inflamed areas while also being resistant to the damaging environment. The creation of this next generation CAR-Treg therapy is of vital importance as there is no effective treatment for ALS.

肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，目前尚无有效的治疗药物. ALS是一种快速进展并最终致命的疾病，在症状发作后两到五年内导致选择性运动神经元丧失和死亡。目前治疗ALS的金标准是利鲁唑，这是一种在20世纪90年代早期开发的没有经过证实的作用机制的药物。作为一种未满足的需求，ALS是药物开发的目标。ALS涉及免疫系统的异常，最显著的变化是T细胞，一种特殊类型的白色血细胞。特别是ALS导致称为T调节细胞或Treg的特化T细胞的损失。这些细胞的作用是抑制免疫反应并保持自我耐受性，即免疫系统将身体识别为非威胁并且只对外来物质产生反应的能力。在ALS中，不仅THBE的数量下降，而且其有效的抑制能力也下降。细胞疗法正处于临床开发阶段，涉及扩大患者来源的TdR，但治疗需要大剂量的TdR，患者在停止输注后很快就会下降。我们认为这是由于高度促炎和促衰老（老化）ALS环境。Reflection Therapeutics开发了一种新的靶向方法，称为CAR-Treg（CAR，嵌合抗原受体），其表现出比传统细胞疗法更好的性能，然而，这些工程细胞发现自己需要解决的恶劣环境。因此，这项资助的主要目的是创造一种CAR-Treg，专门针对发炎区域，同时也能抵抗破坏性环境。由于ALS尚无有效的治疗方法，下一代CAR-Treg疗法的开发至关重要。