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

ICF：使用小鼠模型来确定基因治疗在肾脏疾病治疗中的有效性。

• 批准号: MR/X020975/1
• 负责人: Kevin Marchbank
• 金额: $ 102.07万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX020975%2F1
• 关键词: ICF; Using; mouse; models; establish

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.

我们在国家肾脏补体治疗中心（NRCTC）是最早认识到eculizumab（Soliris，一种阻断我们免疫系统部分补体的药物）是许多罕见血液和肾脏疾病患者的高效治疗方法之一，特别是阵发性睡眠性血红蛋白尿症（PNH）和非典型溶血性尿毒综合征（阿胡斯）。然而，我们也很容易接受依库珠单抗（或其较新的变体ravulizumab）是令人难以置信的昂贵，它并不适用于所有患有阿胡斯的患者，甚至在许多患有类似疾病的患者中也被称为C3肾小球病（C3 G）。依库珠单抗（以及许多其他正在开发的靶向补体的药物）的另一个重要缺点是，它完全关闭了我们免疫系统的重要组成部分，并使接受药物治疗的患者对可能导致脑膜炎的感染高度敏感（>1000倍）。因此，对更好的抗补体药物的需求仍然是明确的，特别是对于C3 G。此外，在更常见的免疫介导的肾脏疾病--伊加肾病（IgAN）中，补体系统的缺陷会增加患者造成的损害和肾衰竭的发生率。这些数据表明，减少这种疾病中的补体活性对患者有益。有几种疗法通过临床试验来阻断补体系统或阻止称为C3的中心分子的激活。补体C3是补体激活旁路途径的重要组成部分，补体激活旁路途径是一个自激活扩增环，并驱动补体的大部分抗菌功能。使用靶向这部分补体系统的药物可能会对感染易感性和对疫苗的不良反应产生显著的副作用。因此，能够重新平衡补体系统，保持关键功能完整的方法可能更安全，耐受时间更长。（HDM-FH;基于称为因子H的血液补体调节剂）它可以恢复补体活性的正常平衡，而不会完全阻断它。我们已经成功地在两种肾脏疾病模型中进行了测试，HDM-FH的基因治疗版本可能是将这种治疗推向临床的最佳方式。我们更广泛的分组和合作者已经成功地将补体蛋白（因子I，FI）基因疗法用于临床，作为年龄相关性变性（AMD，临床试验正在进行-GT 005- Gyroscope/Novartis）的治疗。因此，本研究的目的是提供关于在治疗C3 G、阿胡斯和IgAN中使用/或不使用FI的HDM-FH基因疗法递送的有效性和安全性的详细数据。我们将通过使用常见的C3 G动物模型和最复杂的阿胡斯小动物模型（我们实验室开发的阿胡斯C3功能获得性小鼠模型）以及使用新的IgAN动物模型（基于我们的C3 GOF小鼠并与莱斯特的同事合作开发）或ddY小鼠; IgAN的“金标准”模型来实现这一点。我们将评估治疗预防小鼠发生肾脏疾病的能力，我们将通过测量标准血液和器官功能，通过检查身体不排斥治疗（产生强烈的免疫反应）以及纠正补体调节缺陷不会产生意外影响（即自身免疫）来评估基因治疗的安全性。最后，由于补体系统的激活涉及大多数（如果不是全部的话）炎性疾病（如AMD和癌症控制），并且与许多自身免疫性疾病（如类风湿性关节炎和狼疮）有关，因此使用这些补体过度活性模型对该药物进行进一步验证将为其作为广泛的炎性疾病/病症的潜在治疗进行测试扫清道路。