The Role of Membrane Attack Complex in Atypical Haemolytic Uraemic Syndrome

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Atypical haemolytic uraemic syndrome (aHUS) is a kidney disorder which without treatment rapidly progresses to kidney failure. Until recently, renal transplantation has been contraindicated due to the high recurrence rate. Over the last 20 years research into aHUS has found that it results from over activation of the complement system due to loss of its integral regulation. The complement system is an ancient defence mechanism which protects the body from foreign cells and removes our own damaged ones. In certain conditions, people lack the ability to regulate the complement system, this in turn allows the complement system to attack healthy tissue which subsequently causes disease. In aHUS people have genetic mutations for key complement proteins, this results in a defective protein being produced, which is unable to function normally, this in turn then causes them to develop disease. After research had shown the role of the complement system in aHUS, it led to the use of the drug 'Eculizumab' which has transformed patients' lives. This drugs works by 'switching' off the final pathway of the complement system, preventing the direct attack on healthy cells and preventing the creation of an inflammatory environment. However, the drug is very costly and as it silences one of the body's defences against foreign cells it can make people vulnerable to serious, life threatening infections. In light of the above we have developed a comparative model of aHUS which will allow us to investigate the 'terminal pathway' of the complement system. My experiments will determine which protein of the terminal pathway is responsible for the development of disease. Once we have defined the proteins role in disease we will be able to inhibit its function by using a targeted drug therapy. This will confirm our understanding of the basic mechanisms of the disease whilst simultaneously testing a targeted therapy in a pre-clinical model. This will enable me to develop and deliver a targeted treatment for patients; reducing their risks of increased infection and improve health economics for all. My experiments will provide detailed data regarding the efficacy of the current front line anti-complement therapy in this model, and will heavily inform and dictate whether new complement therapeutics in pre-clinical evaluation can provide better protection for patients in the future. The terminal pathway of the complement system is critical to the development of many more diseases; stemming from sepsis to spinal cord injury. Understanding the roles of the terminal pathway proteins in a model of complement dysregulation (my comparative model of aHUS) will significantly contribute to an improved overall understanding; producing translatable benefits to a wide variety of disease and begin to provide an understanding of anti-complement therapies in these conditions.