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学原因之一，许多患者会出现长期的认知和智力缺陷。免疫系统参与创伤性脑损伤的病理机制已被明确证实。创伤性脑损伤可分为两个不同的阶段：最初的创伤本身(如钝器创伤、冲击伤)和随后发展的继发性炎症。最初的创伤会导致撞击部位的脑细胞死亡，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伤时发生的瘀伤，不同的是，由于产生的压力，头骨内大脑的肿胀对组织的毒性要大得多。创伤性脑损伤后的这种炎症会对脑组织造成第二波损伤，可以杀死与初级损伤本身一样多的脑细胞。这种继发波可能会持续数月甚至数年，从而增加脑损伤的持续时间和严重程度。这项建议旨在预防和修复在第二波创伤性脑损伤中造成的炎症介导的损害。针对免疫系统不同部分的治疗策略到目前为止都失败了，或者只取得了部分成功，主要是因为药物无法越过“血脑屏障”。这一屏障保护大脑免受有害毒素的伤害，但就潜在有益的药物而言，它也阻止了这些药物到达需要它们的大脑。我们已经产生了一种将抗炎剂输送到大脑的新系统，方法是使用一种“基因输送”系统，通过绕过血脑屏障，教脑细胞产生自身需要的抗炎药。我们的数据表明，我们可以增加治疗小鼠大脑中的“调节性T细胞”的数量。这些是抗炎的白血球，能主动减少大脑中的炎症，促进修复。使用创伤性脑损伤的小鼠模型，这种治疗方法将损伤后的损伤减少了50%。由于目前还没有预防创伤性脑损伤患者继发性脑损伤的药物，因此，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损失，改善照顾者、家人和朋友的生活质量，并通过预防阻碍独立工作和生活能力的长期残疾来减轻伤害的经济负担。在这笔赠款中，我们正在寻求开发这种商业化的治疗方法。该药物目前正在优化用于小鼠，并需要优化的人性化版本。我们还需要启动人体试验的监管过程和生产临床级药物的生产过程。在这个项目完成后，我们将拥有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.