Understanding the Properdin Paradox using C3 D1115N (gain-of-function) knock-in mice

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We at the National Renal Complement Therapeutic Centre (NRCTC) were one of the first to recognise that eculizumab (Soliris, a drug that blocks part of our immune system known as complement) is a highly effective treatment in many patients with rare blood and kidney diseases, particularly paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS). However, we also readily accept that eculizumab is incredibly expensive, it does work on all patients with aHUS (or indeed in many patients with a related disease known as C3 glomerulopathy) and because it completely switches off an important component of our immune system, it leaves patients treated with the drug highly susceptible (>1000 fold more so) to infections that can cause meningitis. Therefore, the need for better anti-complement drugs is clear. Many such drugs are in development that target complement component C3. C3 is at heart of the complement system, an important part of the alternative pathway of complement activation which is a self-activating amplification loop and drives much of the anti-bacterial function of complement. Use of drugs that target this part of the complement system may have significant side effects with respect to susceptibility to infection and poor response to vaccines.Models systems to test drugs that target C3 in a comprehensive, realistic manner, with respect to aHUS, are generally lacking. Over the last decade we have successfully generated several unique copies of mouse C3 molecules based on changes (or mutations) found in human C3 that associated with aHUS. In doing so, we demonstrated that we could transfer functional changes from patients to a mouse model. In this case, we generated a C3 molecule which was hyperactive. Mice with this change on both gene copies of C3 rapidly develop aHUS. Our analysis confirms that blockade of the complement system in a manner equivalent to use of eculizumab in man completely protects mice from aHUS and therefore validates the model for testing of other anti-complement drugs. Recent work by our colleagues has suggested that drugs that block the function of another protein in the complement system, known as properdin, may prevent aspects of aHUS and indeed, may be useful in PNH. However, other studies examining the blockade of properdin in C3 glomerulopathy were catastrophic. This leaves important questions around the suitability of use of anti-properdin drugs in aHUS to be resolved. Furthermore, addressing these questions may have significant impact on our knowledge of properdin function overall and allow better choice of anti-complement drug use in more general conditions such as common autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus or indeed during organ transplantation.Therefore, the aim of this study is to provide detailed data regarding the efficacy of using anti-properdin drugs in the treatment of aHUS using the most sophisticated small animal model of aHUS available. To compare these findings to the current front line anti-complement drugs. To assess whether new anti-complement drugs can provide better protection than existing drugs regardless of the complement protein variant that caused the disease, i.e. establish the need or provide the rationale for a detailed framework for personalised medicine in the treatment of aHUS patients for the future. Finally, as activation of the complement system is involved in most, if not all, inflammatory conditions (such as age-related macular degeneration and control of cancer) and is linked to many autoimmune diseases (such as rheumatoid arthritis and lupus), the further validation of this comparative model, which has hyperactive C3 at its heart, will cement its place as the premier model to analyse the role of complement activation in the progression, and the treatment, of a wide range of inflammatory diseases/conditions.