New therapeutic strategies in the treatment of traumatic brain injury by targeting the LEctin Activation Pathway of complement

针对补体凝集素激活途径治疗创伤性脑损伤的新治疗策略

• 批准号: MR/R002983/1
• 负责人: Wilhelm Schwaeble
• 金额: $ 24.63万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR002983%2F1
• 关键词: New; therapeutic; strategies; treatment; traumatic

Traumatic Brain Injury (TBI) is an injury to the brain caused by a trauma to the head (head injury). The main causes of TBI are road traffic accidents, assaults, falls and accidents at home or at work. An the UK, approximately 1 million cases with head injury are seen in Accident and Emergency Clinics per year of which 15% require hospitalisation. The damage caused by TBI can be temporary or permanent leading to various degrees of physical, cognitive, and behavioural/emotional impairments or death. The outcome of TBI is determined by the severity of the initial injury and by the degree of the inflammatory response following the injury. Limiting the inflammatory response following the injury is a desirable neuroprotective treatment that can significantly improve the clinical outcome of TBI. This project is based the observationthat a defined pro-inflammatory pathway of the innate immune defence, called the lectin activation pathway of complement, plays a key role in driving inflammation following injury and the investigators have identified the key enzyme that drives this inflammatory response following injury. This enzyme is exclusively made by liver cells and reaches other organs through the blood supply where it is present at very low plasma levels. An effective and long-lasting therapeutic depletion of this enzyme can be achieved by administration of a monoclonal antibody which significantly reduces inflammatory tissue loss as previously shown in experimental models of stroke, myocardial infarction and renal transplantation. The preliminary results in experimental TBI model clearly imply that MASP-2 inhibition will effectively limit post-traumatic inflammation and loss of CNS tissue. This project is likely to deliver the proof-of-principal data required to advance a new and highly neuroprotective clinical therapy to reduce morbidity and mortality following TBI.

创伤性脑损伤（TBI）是由头部外伤（头部损伤）引起的脑损伤。创伤性脑损伤的主要原因是道路交通事故、袭击、跌倒以及家中或工作场所发生的事故。在英国，每年约有100万例头部受伤病例在事故和急诊诊所就诊，其中15%需要住院治疗。脑外伤造成的损害可以是暂时的，也可以是永久性的，导致不同程度的身体、认知和行为/情感障碍或死亡。TBI的预后取决于初始损伤的严重程度和损伤后炎症反应的程度。限制损伤后的炎症反应是一种理想的神经保护治疗，可以显著改善创伤性脑损伤的临床结果。这个项目是基于观察先天免疫防御的促炎途径，称为补体凝集素激活途径，在损伤后驱动炎症中起关键作用，研究人员已经确定了驱动损伤后炎症反应的关键酶。这种酶仅由肝细胞产生，并通过血液供应到达其他器官，在那里它以非常低的血浆水平存在。这种酶的有效和持久的治疗性消耗可以通过给药单克隆抗体来实现，单克隆抗体可以显着减少炎症组织的损失，正如先前在中风、心肌梗死和肾移植的实验模型中所显示的那样。实验性TBI模型的初步结果清楚地表明，抑制MASP-2可以有效地限制创伤后炎症和中枢神经系统组织的损失。该项目可能会提供所需的主要证据数据，以推进一种新的高度神经保护的临床疗法，以降低TBI后的发病率和死亡率。

项目成果

Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury, with MASP-2 playing a major role.

• DOI: 10.1186/s40478-020-01041-1
• 发表时间: 2020-10-28
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Mercurio D;Oggioni M;Fumagalli S;Lynch NJ;Roscher S;Minuta D;Perego C;Ippati S;Wallis R;Schwaeble WJ;De Simoni MG
• 通讯作者: De Simoni MG