The complement system is a key component of innate immunity, but impaired regulation influences disease susceptibility, including age-related macular degeneration and some kidney diseases. While complete complement inhibition has been used successfully to treat acute kidney disease, key unresolved challenges include strategies to modulate rather than completely inhibit the system and to deliver therapy potentially over decades. Elevating concentrations of complement factor I (CFI) restricts complement activation in vitro and this approach was extended in the current study to modulate complement activation in vivo. Sustained increases in CFI levels were achieved using an adeno-associated virus (AAV) vector to target the liver, inducing a 4- to 5-fold increase in circulating CFI levels. This led to decreased activity of the alternative pathway as demonstrated by a reduction in the rate of inactive C3b (iC3b) deposition and more rapid formation of C3 degradation products. In addition, vector application in a mouse model of systemic lupus erythematosus (NZBWF1), where tissue injury is, in part, complement dependent, resulted in reduced complement C3 and IgG renal deposition. Collectively, these data demonstrate that sustained elevation of CFI reduces complement activation in vivo providing proof-of-principle support for the therapeutic application of AAV gene delivery to modulate complement activation.

中文翻译：

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腺相关病毒载体基因递送提高因子 I 水平并下调体内补体替代途径

补体系统是先天免疫的关键组成部分，但调节受损会影响疾病易感性，包括与年龄相关的黄斑变性和一些肾脏疾病。虽然完全的补体抑制已成功用于治疗急性肾病，但尚未解决的关键挑战包括调节而不是完全抑制系统的策略，并可能在数十年内提供治疗。提高补体因子 I (CFI) 的浓度会限制体外补体激活，并且该方法在当前研究中被扩展以调节体内补体激活. 使用腺相关病毒 (AAV) 载体靶向肝脏实现了 CFI 水平的持续增加，导致循环 CFI 水平增加 4 至 5 倍。这导致替代途径的活性降低，如非活性 C3b (iC3b) 沉积速率的降低和 C3 降解产物的更快形成所证明的。此外，将载体应用于系统性红斑狼疮 (NZBWF1) 小鼠模型（其中组织损伤部分依赖补体）导致补体 C3 和 IgG 肾脏沉积减少。总的来说，这些数据表明 CFI 的持续升高会降低体内补体活化，从而为 AAV 基因递送以调节补体活化的治疗应用提供原理证明支持。