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）是由头部创伤引起的大脑损伤（头部损伤）。 TBI的主要原因是道路交通事故，袭击，跌倒和在家中或工作中发生。英国，每年有100万例头部受伤的案件，每年有15％的人需要住院。由TBI造成的损害可能是暂时的或永久的，导致各种程度的身体，认知和行为/情绪障碍或死亡。 TBI的结果取决于最初损伤的严重程度和受伤后的炎症反应程度。限制损伤后的炎症反应是一种理想的神经保护治疗，可以显着改善TBI的临床结果。该项目是基于观察到的，该观察是一种先天免疫防御的促炎途径，称为补体的凝集素激活途径，在受伤后驱动炎症中起着关键作用，研究人员已经确定了驱动这种炎症后炎症反应的关键酶。该酶仅由肝细胞制成，并通过血浆水平非常低的血液供应到达其他器官。可以通过给予单克隆抗体来实现该酶的有效且长期的治疗性耗竭，该抗体可显着减少炎症组织损失，如先前在中风模型，心肌梗塞和肾脏移植的实验模型中所示。实验性TBI模型的初步结果显然表明MASP-2抑制作用将有效地限制创伤后炎症和中枢神经系统组织的丧失。该项目可能会提供促进新的和高度神经保护临床疗法的主要数据证明数据，以降低TBI后发病率和死亡率。

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