Development of a humanised delivery system for interleukin 2 to treat traumatic brain injury

开发白细胞介素2人源化递送系统来治疗创伤性脑损伤

• 批准号: MR/X029166/1
• 负责人: Adrian Liston
• 金额: $ 82.13万
• 依托单位: University of Cambridge
• 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=MR%2FX029166%2F1
• 关键词: Development; humanised; delivery; system; interleukin

Traumatic brain injury is one of the leading neurological causes of disability in the world, with many patients developing long-lasting cognitive and mental deficits. The involvement of the immune system in the pathology of traumatic brain injury has clearly been established. Traumatic brain injury can be divided into two distinct stages: the initial trauma itself (e.g. blunt force trauma, blast injuries) and a secondary inflammation that develops afterwards. The initial trauma causes cell death in the brain at the impact site, releasing signals that drive an inflammatory response. This inflammation is similar to the bruising that occurs when an ankle or knee is twisted, with the difference being the swelling of the brain within the skull is much more toxic to the tissue, due to the pressure created. This inflammation following a traumatic brain injury causes a secondary wave of damage generation to the brain tissue, which can kill as many brain cells as the primary injury itself. This secondary wave can continue for months or even years, increasing the duration and severity of the brain damage. This proposal seeks to prevent and repair the inflammation-mediated damage caused during this second wave of traumatic brain injury. Therapeutic strategies aimed at different parts of the immune system thus far failed, or were only partially successful, largely because of the inability of drugs to cross over the "blood-brain barrier". This barrier protects the brain from harmful toxins, but in the case of potentially beneficial drugs it also prevents those drugs from reaching the brain where they are needed. We have generated a new system for delivering anti-inflammatory agents to the brain, by using a "gene delivery" system that teaches brain cells to produce the anti-inflammatory drug that the need themselves, bypassing the blood-brain barrier. Our data demonstrates that we can increase the number of "regulatory T cells" in the brain of treated mice. These are anti-inflammatory white blood cells that actively reduce inflammation in the brain and promote repair. Using a mouse model of traumatic brain injury, this treatment reduced the damage following injury by 50%. As there are currently no drugs available that prevent traumatic brain injury patients from secondary brain damage, a new drug with 50% protective capacity would have enormous social and economic impact, reducing the long-term cognitive loss in patients, improving the quality of life of carers, family and friends, and reducing the economic burden of injury by preventing long-term disability that impedes the ability to work and live independently. In this grant we are seeking to develop this therapeutic approach for commercialisation. The drug is currently optimised for use in mice, and requires optimisation of a humanised version. We also need to initiate the regulatory process for testing in humans and the production process to manufacture clinical-grade drug. At the completion of this program we will have the scientific data and regulatory approvals required to move forward with clinical trials, with the trial funding raised through private capital.

创伤性脑损伤是世界上残疾的主要神经系统损伤之一，许多患者患有持久的认知和精神缺陷。显然已经建立了免疫系统参与创伤性脑损伤病理学的参与。创伤性脑损伤可以分为两个不同的阶段：初始创伤本身（例如钝力创伤，爆炸损伤）和随后发生的继发性炎症。最初的创伤会导致撞击部位的大脑细胞死亡，从而释放出驱动炎症反应的信号。这种炎症类似于扭曲脚踝或膝盖时发生的瘀伤，由于产生的压力，颅骨内大脑内的肿胀对组织的毒性更大。创伤性脑损伤后这种炎症会导致脑组织的损伤产生次要波，这可能会杀死与主要损伤本身一样多的脑细胞。这种次要波可以持续数月甚至几年，从而增加了脑损伤的持续时间和严重程度。该提案旨在预防和修复第二次创伤性脑损伤造成的炎症介导的损害。到目前为止，针对免疫系统不同部位的治疗策略失败了，或者只是部分成功，这主要是因为药物无法跨越“血脑屏障”。这种障碍可保护大脑免受有害毒素的影响，但在潜在的有益药物的情况下，它也可以防止这些药物进入需要的大脑。我们通过使用一种“基因递送”系统来教授脑细胞生产需要本身的抗炎药，绕过血脑屏障，从而绕开了一个新系统，以绕过脑细胞产生抗炎药，从而绕过血脑屏障，从而绕开了脑细胞，从而绕开了脑细胞。我们的数据表明，我们可以增加治疗小鼠大脑中“调节性T细胞”的数量。这些是抗炎的白细胞，可积极减少大脑的炎症并促进修复。使用脑外伤的小鼠模型，这种治疗可将损伤后的损伤减少50％。由于目前尚无可预防脑损伤患者免受继发性脑损伤的药物，具有50％保护能力的新药将对社会和经济影响产生巨大的影响，从而减少患者的长期认知损失，从而改善护理人员，家人和朋友的生活质量，并通过降低长期残障的经济负担，从而降低长期残障的能力，从而影响与实用和实时实现的能力。在这笔赠款中，我们正在寻求开发这种商业化的治疗方法。目前，该药物已在小鼠中进行优化，需要优化人性化版本。我们还需要启动人类测试的调节过程和生产临床级药物的生产过程。该计划完成后，我们将拥有进行临床试验进行的科学数据和监管批准，并通过私人资本筹集了试验资金。