Development of a C3 Humanized Rat as a New Model for Evaluating Novel C3 Inhibitors.

IF 4.7 3区 医学 Q2 IMMUNOLOGY Journal of Innate Immunity Pub Date : 2024-01-01 Epub Date: 2023-11-30 DOI:10.1159/000534963
Jin Y Chen, Lingjun Zhang, Maojing Yang, Elizabeth D Hughes, Zachary T Freeman, Thomas L Saunders, Feng Lin
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Abstract

Introduction: C3 is central for all complement activation pathways, thus making it an attractive therapeutic target. Many C3-targeted agents are under extensive development with one already approved for clinical use. However, most, if not all, C3 inhibitors are human or nonhuman primate C3-specific, making evaluating their efficacies in vivo before a clinical trial extremely difficult and costly.

Methods: We first studied the compatibility of human C3 in the rat complement system, then developed a C3 humanized rat using the CRISPR/Cas9 technology. We thoroughly characterized the resultant human C3 humanized rats and tested the treatment efficacy of an established primate-specific C3 inhibitor in a model of complement-mediated hemolysis in the C3 humanized rats.

Results: We found that supplementing human C3 protein into the C3-deficient rat blood restored its complement activity, which was inhibited by rat factor H or compstatin, suggesting that human C3 is compatible to the rat complement system. The newly developed C3 humanized rats appeared healthy and expressed human but not rat C3 without detectable spontaneous C3 activation. More importantly, complement-mediated hemolysis in the C3 humanized rats was also inhibited by compstatin both in vitro and in vivo.

Conclusion: The successfully developed C3 humanized rats provided a much-desired rodent model to evaluate novel C3 inhibitors in vivo as potential drugs.

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C3人源化大鼠作为评价新型C3抑制剂的新模型的建立。
C3是所有补体激活途径的中枢,因此是一个有吸引力的治疗靶点。许多靶向c3的药物正在广泛开发中,其中一种已经被批准用于临床。然而,大多数(如果不是全部的话)C3抑制剂是人类或非人类灵长类动物C3特异性的,这使得在临床试验之前评估其体内疗效极其困难和昂贵。方法:首先研究人C3在大鼠补体系统中的相容性,然后利用CRISPR/Cas9技术培养C3人源化大鼠。我们彻底表征了由此产生的人C3人源化大鼠,并在补体介导的C3人源化大鼠溶血模型中测试了一种已建立的灵长类特异性C3抑制剂的治疗效果。结果:我们发现,在缺乏C3的大鼠血液中补充人C3蛋白可以恢复其补体活性,而补体活性被大鼠因子H或压缩抑素抑制,这表明人C3与大鼠补体系统兼容。新发育的C3人源化大鼠表现健康,表达人C3而非大鼠C3,没有可检测到的自发C3激活。更重要的是,补体介导的溶血在C3人源化大鼠体内和体外均被压缩抑素抑制。结论:成功培育的C3人源化大鼠为体内评价新型C3抑制剂作为潜在药物提供了理想的啮齿类动物模型。
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来源期刊
Journal of Innate Immunity
Journal of Innate Immunity 医学-免疫学
CiteScore
10.50
自引率
1.90%
发文量
35
审稿时长
7.5 months
期刊介绍: The ''Journal of Innate Immunity'' is a bimonthly journal covering all aspects within the area of innate immunity, including evolution of the immune system, molecular biology of cells involved in innate immunity, pattern recognition and signals of ‘danger’, microbial corruption, host response and inflammation, mucosal immunity, complement and coagulation, sepsis and septic shock, molecular genomics, and development of immunotherapies. The journal publishes original research articles, short communications, reviews, commentaries and letters to the editors. In addition to regular papers, some issues feature a special section with a thematic focus.
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