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

使用 C3 D1115N（功能获得）敲入小鼠了解备解素悖论

• 批准号: MR/S025502/1
• 负责人: Kevin Marchbank
• 金额: $ 58.03万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS025502%2F1
• 关键词: Understanding; Properdin; Paradox; using; C3

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.

我们在国家肾补体治疗中心（NRCTC）是第一个认识到eculizumab （Soliris，一种阻断我们部分免疫系统的药物，称为补体）是一种非常有效的治疗许多罕见血液和肾脏疾病的患者，特别是突发性夜间血红蛋白尿（PNH）和非典型溶血性尿毒综合征（aHUS）。然而，我们也很容易接受eculizumab非常昂贵的事实，它对所有aHUS患者（或许多患有C3肾小球病的相关疾病的患者）都有效，而且由于它完全关闭了我们免疫系统的一个重要组成部分，它使接受该药治疗的患者极易感染可引起脑膜炎的感染（比这高出1000倍）。因此，需要更好的抗补体药物是明确的。许多这类药物正在开发中，目标是补体成分C3。C3是补体系统的核心，是补体激活替代途径的重要组成部分，补体激活是一个自我激活的扩增环，并驱动补体的许多抗菌功能。使用针对这部分补体系统的药物可能会有明显的副作用，如对感染的易感性和对疫苗的不良反应。就aHUS而言，通常缺乏以全面、现实的方式测试针对C3的药物的模型系统。在过去的十年中，我们已经成功地基于人类C3中发现的与aHUS相关的变化（或突变），生成了几种独特的小鼠C3分子拷贝。通过这样做，我们证明了我们可以将患者的功能变化转移到小鼠模型中。在这个例子中，我们生成了一个非常活跃的C3分子。在两个C3基因拷贝上发生这种变化的小鼠迅速发展为aHUS。我们的分析证实，阻断补体系统的方式相当于在人体内使用eculizumab，完全保护小鼠免受aHUS的侵害，因此验证了测试其他抗补体药物的模型。我们的同事最近的工作表明，阻断补体系统中另一种蛋白质功能的药物，被称为properdin，可能会预防aHUS的某些方面，实际上，可能对PNH有用。然而，其他研究在C3肾小球病变中检查properdin阻断是灾难性的。这就留下了一些重要的问题，围绕在aHUS中使用抗properdin药物的适用性有待解决。此外，解决这些问题可能会对我们对正常功能的整体认识产生重大影响，并允许在更一般的情况下（如风湿性关节炎和系统性红斑狼疮等常见自身免疫性疾病）或器官移植期间更好地选择抗补体药物的使用。因此，本研究的目的是利用目前最复杂的aHUS小动物模型，提供有关使用抗properdin药物治疗aHUS疗效的详细数据。将这些发现与当前一线抗补体药物进行比较。评估新的抗补体药物是否能比现有药物提供更好的保护，而不考虑引起疾病的补体蛋白变异，即确定未来治疗aHUS患者个性化药物的详细框架的必要性或提供理由。最后，由于补体系统的激活参与了大多数（如果不是全部的话）炎症（如年龄相关性黄斑变性和癌症控制），并与许多自身免疫性疾病（如类风湿关节炎和狼疮）有关，进一步验证这个以过度活跃的C3为核心的比较模型，将巩固其作为分析补体激活在进展和治疗中的作用的首要模型的地位。多种炎症性疾病/病症的

项目成果

Contribution of animal models to the mechanistic understanding of Alternative Pathway and Amplification Loop (AP/AL)-driven Complement-mediated Diseases.

• DOI: 10.1111/imr.13141
• 发表时间: 2023-01
• 期刊: Immunological reviews
• 影响因子: 8.7

TREATMENT OF THE C3 GAIN-OF-FUNCTION MOUSE MODEL OF AHUS THROUGH INHIBITION OF C5a, PROPERDIN OR THE C3 CONVERTASE

通过抑制 C5a、备解素或 C3 转化酶来治疗 AHUS 的 C3 功能获得小鼠模型

• 发表时间: 2019
• 期刊: MOLECULAR IMMUNOLOGY
• 影响因子: 3.6
• 作者: Smith-Jackson Kate

82 Using the C3 gain-of-function mouse model of aHUS as a complement therapeutic testbed to enable precision medicine for complement mediated atypical haemolytic uraemic syndrome

82 使用 aHUS 的 C3 功能获得小鼠模型作为补体治疗试验台，以实现补体介导的非典型溶血性尿毒综合征的精准医疗

• DOI: 10.1016/j.imbio.2023.152533
• 发表时间: 2023
• 期刊: Immunobiology
• 影响因子: 2.8
• 作者: Smith-Jackson K

118 Atypical haemolytic uraemic syndrome in the era of complement inhibiting therapy: The UK national cohort experience

118 补体抑制治疗时代的非典型溶血性尿毒综合征：英国国家队列经验

• DOI: 10.1016/j.imbio.2023.152569
• 发表时间: 2023
• 期刊: Immunobiology
• 影响因子: 2.8
• 作者: Brocklebank V

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice.

• DOI: 10.3389/fimmu.2021.752916
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Kamala O;Malik TH;Hallam TM;Cox TE;Yang Y;Vyas F;Luli S;Connelly C;Gibson B;Smith-Jackson K;Denton H;Pappworth IY;Huang L;Kavanagh D;Pickering MC;Marchbank KJ
• 通讯作者: Marchbank KJ