ICF: Using mouse models to establish the effectiveness of gene therapy in the treatment of renal diseases.

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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 (or its newer variant ravulizumab) is incredibly expensive, it does not work in all patients with aHUS or indeed in many patients with a similar disease known as C3 glomerulopathy (C3G). Another important draw back of eculizumab (and many other drugs in development that target complement) is that it completely switches off important components of our immune system and 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 remains clear, particularly for C3G. Furthermore, in IgA nephropathy (IgAN), a more common immune mediated renal disease, defects in the complement system increase the damage caused and the rate of renal failure in patients. The data suggest that reducing complement activity in this disease would be beneficial to patients.There are several therapies coming through clinical trails which block the complement system or prevent activation of the central molecule called C3. C3 is 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. Therefore, approaches that can re-balance the complement system, leaving key functionality intact, would potentially be safer and tolerated for longer.In our recent work, we have developed a 'drug' - homodimeric minimal FH (HDM-FH; based on a blood based regulator of complement called Factor H) that can restore the normal balance of complement activity without completely blocking it. We have successfully tested it in two models of renal disease and shown that a gene therapy version of HDM-FH could be the optimal way to bring this therapy to clinic. Our wider grouping and collaborators have already had success with taking a complement protein (Factor I, FI) gene therapy to clinic, as a treatment of age-related degeneration (AMD, clinical trails ongoing - GT005 - Gyroscope/Novartis). Therefore, the aim of this study is to provide detailed data regarding the effectiveness and safety of gene therapy delivery of HDM-FH with/or without FI in the treatment of C3G, aHUS and IgAN. We will achieve this by using a common animal model of C3G and the most sophisticated small animal model of aHUS available (the C3 gain-of-function mouse model of aHUS, developed in our lab) as well as using an new animal model of IgAN (based on our C3 GOF mouse and developed in collaboration with colleagues in Leicester) or in the ddY mouse; the 'gold standard' model of IgAN. We will assess the ability of the therapies to prevent kidney disease from developing in the mice, we will assess the safety of the gene therapy by measuring standard blood and organ functionality, by checking that the body does not reject the therapy (mount a strong immune response) and that correcting the deficit in complement regulation does not have unintended affects i.e. autoimmunity. Finally, as activation of the complement system is involved in most, if not all, inflammatory conditions (such as AMD and control of cancer) and is linked to many autoimmune diseases (such as rheumatoid arthritis and lupus), the further validation of this drug using these models of complement over activity, will clear the way to its testing as a potential treatment in a wide range of inflammatory diseases/conditions.