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

创伤性脑损伤是世界上导致残疾的主要神经系统原因之一，许多患者会出现长期的认知和精神缺陷。免疫系统在创伤性脑损伤病理中的作用已被明确确立。创伤性脑损伤可分为两个不同的阶段：初始创伤本身（如钝器外伤、爆炸伤）和随后发生的继发性炎症。最初的创伤会导致大脑中撞击部位的细胞死亡，释放出驱动炎症反应的信号。这种炎症类似于脚踝或膝盖扭曲时产生的瘀伤，不同之处在于，由于产生的压力，颅骨内的大脑肿胀对组织的毒性要大得多。这种创伤性脑损伤后的炎症会对脑组织造成二次损伤，这可能会杀死与原发性损伤本身一样多的脑细胞。这种第二波可以持续数月甚至数年，增加了脑损伤的持续时间和严重程度。本研究旨在预防和修复第二波创伤性脑损伤中炎症介导的损伤。迄今为止，针对免疫系统不同部位的治疗策略都失败了，或者只是部分成功，这主要是因为药物无法跨越“血脑屏障”。这种屏障保护大脑免受有害毒素的侵害，但在潜在有益药物的情况下，它也阻止这些药物到达大脑需要它们的地方。我们发明了一种新的系统，通过一种“基因传递”系统，教会脑细胞绕过血脑屏障，自己产生所需的抗炎药物，从而将抗炎药物输送到大脑。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，可以积极减少大脑中的炎症，促进修复。在创伤性脑损伤小鼠模型中，这种治疗将损伤后的损伤减少了50%。由于目前没有药物可以防止创伤性脑损伤患者继发性脑损伤，一种具有50%保护能力的新药将产生巨大的社会和经济影响，减少患者的长期认知丧失，提高护理人员、家人和朋友的生活质量，并通过预防妨碍工作和独立生活能力的长期残疾来减轻损伤的经济负担。在这笔拨款中，我们正在寻求开发这种商业化的治疗方法。该药物目前针对小鼠进行了优化，并需要优化人源化版本。我们还需要启动人体试验和生产过程的监管程序，以生产临床级药物。在这个项目完成后，我们将获得推进临床试验所需的科学数据和监管批准，试验资金将通过私人资本筹集。

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.