Jones Aarin, Sun Aixu, Yang Hua, Latuszek Adrianna, Negron Nicole, Shi Peisheng, Fury Wen, Lehmann Guillermo L, Hu Ying, Sagdullaev Botir
Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA.
Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA.
Exp Eye Res. 2025 Sep;258:110433. doi: 10.1016/j.exer.2025.110433. Epub 2025 May 24.
Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic and pathophysiological studies have implicated that complement pathway dysfunction is a key contributor to progressive vision loss in AMD. Though the association between complement and AMD is recognized, numerous anti-complement therapeutics that had been tested in rodent model systems had limited success in clinical trials. Understanding complement factor production and site of action in ocular pathophysiology is critical for the development of efficacious therapeutics. However, our limited understanding of how these aspects of complement biology vary across species restricts our ability to predict clinical outcomes from studies using animal models. Here, we integrated transcriptomic and immunohistochemical assays to understand the expression and localization of core complement components (complement factor H (FH), complement 3 (C3), and complement 5 (C5)) between ocular tissues of rodent, non-human primate, and human species. We found that complement distribution varied significantly across the studied species, with the most striking differences observed in the FH. While rodents expressed Cfh, an alternative pathway inhibitor, mainly in the RPE, CFH expression in primate eyes was primarily confined to the choroid. These differences were consistent at the protein level, with rodent FH localized in the RPE and primate FH within the choriocapillaris, choroid and sclera. Regarding C5, a terminal complement pathway component, we observed minimal ocular mRNA levels in all three species. However, we observed detectable protein levels in the RPE in rodents and the choroid in humans. Next, C3 mRNA transcripts and C3 protein exhibited similar distribution in the choroid in both rodent and primate eyes. Together, our findings highlight key differences and similarities between rodent and primate complement biology that may offer insights into the translatability of animal models and inform the design of effective therapeutics.
年龄相关性黄斑变性（AMD）是导致失明的主要原因。遗传和病理生理学研究表明，补体途径功能障碍是AMD中导致视力渐进性丧失的关键因素。尽管补体与AMD之间的关联已得到认可，但在啮齿动物模型系统中测试过的众多抗补体疗法在临床试验中的成功率有限。了解补体因子在眼部病理生理学中的产生和作用部位对于开发有效的治疗方法至关重要。然而，我们对补体生物学的这些方面在不同物种间如何变化的了解有限，这限制了我们从动物模型研究中预测临床结果的能力。在这里，我们整合了转录组学和免疫组织化学分析，以了解啮齿动物、非人灵长类动物和人类眼部组织之间核心补体成分（补体因子H（FH）、补体3（C3）和补体5（C5））的表达和定位。我们发现，在所研究的物种中，补体分布存在显著差异，其中FH的差异最为明显。虽然啮齿动物主要在视网膜色素上皮（RPE）中表达替代途径抑制剂Cfh，但灵长类动物眼中的CFH表达主要局限于脉络膜。这些差异在蛋白质水平上也是一致的，啮齿动物的FH定位于RPE，而灵长类动物的FH位于脉络膜毛细血管、脉络膜和巩膜内。关于终末补体途径成分C5，我们在所有三个物种的眼中均观察到极低的mRNA水平。然而，我们在啮齿动物的RPE和人类的脉络膜中观察到了可检测到的蛋白质水平。接下来，C3 mRNA转录本和C3蛋白在啮齿动物和灵长类动物眼睛的脉络膜中表现出相似的分布。总之，我们的研究结果突出了啮齿动物和灵长类动物补体生物学之间的关键差异和相似之处，这可能为动物模型的可转化性提供见解，并为有效治疗方法的设计提供参考。
