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

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 observation
that 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.

The present research programs aims to define the therapeutic utility of an inhibitory antibody that specifically inhibits a plasma based serine protease called MASP-2 (for Mannan binding lectin Associated Serine Protease-2) of the lectin activation pathway of the complement system, a component of the innate immune system. Inhibiting MASP-2 proved to significantly reduce post ischaemic reperfusion injury (IRI) and post-traumatic inflammation in experimental mouse models of stroke, renal transplantation, renal ischaemia and gastrointestinal ischaemia resulting in a significant reduction of tissue loss and loss of organ functions. MASP-2 inhibition also proved to be an effective treatment for thrombotic pathologies first shown in model of LPS induced thrombosis and FITC-dextran and light induced model of endothelial injury leading to thrombosis in the low pressure blood circulatory system. A clinical candidate inhibitor for MASP-2, a recombinant therapeutic antibody called OMS721 has been assessed in phase 2 and 3 clinical trial in patients with life-threatening microangiopathies, such as thrombotic thrombocytopenic purpura (TTP) and atypical Haemolytic Uraemia Syndrome (aHUS). The treatment proved to be highly successful and significantly improved the clinical outcome of these severe clinical conditions improving all clinical parameters of disease severity without increasing the risk of blood loss by interfering with plasma agglutination. The present research programme will define the windows of therapeutic efficacy to improve the outcome of traumatic brain injury by reducing post-traumatic inflammation and inflammatory loss of CNS tissue and CNS functions.

Traumatic brain injury (TBI) is an important global public health problem. An estimated 57 million people have been hospitalised after suffering TBI worldwide annually and the annual cost of care and loss of productivity through the long-term effects of TBI have been estimated to mount up to more than 60 Billion Dollars in the US alone. The outcome of TBI depends primarily on the severity and impact of the initial insult, but is greatly influenced by the prevention of secondary insults through post-traumatic complications like post-traumatic inflammation or post-traumatic infection of the primary injury site. While little can be done to limit the severity of the initial injury, to limit the secondary inflammatory response to TBI is crucial, since inflammation causes swelling and edema which in turn induces leucocyte infiltration and ischaemic secondary injury of CNS tissue. This research project studies the molecular event leading to post traumatic inflammation and assesses the efficiency of a novel therapy to limit post traumatic inflammation by targeting the pro-inflammatory response of the innate immune system to damaged cells and tissues. This proposed novel therapy utilises a recombinant antibody to the key enzyme of the innate immune response system, a low abundant serine protease called MASP-2 which translates the binding of recognition complexes of the innate immune system to the surface of injured cells into a cascade of enzymatic events that attract to and activate immune cells at the site of injury to promote inflammation. Inflammation in turn leads to a hostile environment for the survival of neuronal cells and tissue and causes edema and swelling which in turn causes ischaemia and disruption of blood flow in an enclosed environment like the brain, which offers little space for inflammation related tissue expansion. In other models of brain injury, like models of experimentally induced transient ischaemia of the brain (i.e. stroke), the investigatory were able to demonstrate that the therapeutic inhibition of MASP-2 has a significant neuroprotective effect, limiting the size of the final infarct area and improving the outcome by limiting the neurological impairment and loss of cognitive functions. We expect to see a significant therapeutic effect of MASP-2 inhibition following TBI and expect this work to define the window of therapeutic opportunity to improve the clinical outcome of TBI by limiting post-traumatic inflammation and tissue loss.