Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo.
Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo.
复制标题
在体内用脂质纳米颗粒系统地传递了未修饰和假氨酸修饰的mRNA的功效和免疫原性。
DOI：
10.1016/j.biomaterials.2016.09.006
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发表时间：
2016-12
期刊：
影响因子：
14
通讯作者：
Anderson DG
中科院分区：
文献类型：
--
作者：
Kauffman KJ;Mir FF;Jhunjhunwala S;Kaczmarek JC;Hurtado JE;Yang JH;Webber MJ;Kowalski PS;Heartlein MW;DeRosa F;Anderson DG
信使核糖核酸在治疗需要蛋白质表达的疾病方面具有广阔的潜力。然而，信使核糖核酸也可以诱导具有相关毒性的免疫反应。假性尿苷取代尿苷碱基被认为可以调节mRNA的免疫原性和效力。在这里，我们探索了脂类纳米颗粒配方的未修饰和假性尿苷修饰的mRNAs在体内系统注射的免疫反应和活性。与未修饰的mRNAs相比，与未修饰的mRNAs相比，假性尿苷修饰的mRNAs对脂质纳米粒的物理性质、体内蛋白表达或mRNA的免疫原性没有显著影响，但降低了体外转染率。观察到对mRNA的一过性细胞外天然免疫反应的指标，包括中性粒细胞增多，髓系细胞激活，以及四种血清细胞因子的上调。这项研究提供了对信使核糖核酸脂质纳米粒的免疫反应的洞察力，并提示对于信使核糖核酸在肝脏中的治疗应用来说，伪尿苷修饰可能是不必要的。
mRNA has broad potential for treating diseases requiring protein expression. However, mRNA can also induce an immune response with associated toxicity. Replacement of uridine bases with pseudouridine has been postulated to modulate both mRNA immunogenicity and potency. Here, we explore the immune response and activity of lipid nanoparticle-formulated unmodified and pseudouridine-modified mRNAs administered systemically in vivo. Pseudouridine modification to mRNA had no significant effect on lipid nanoparticle physical properties, protein expression in vivo, or mRNA immunogenicity compared to unmodified mRNA when delivered systemically with liver-targeting lipid nanoparticles, but reduced in vitro transfection levels. Indicators of a transient, extracellular innate immune response to mRNA were observed, including neutrophilia, myeloid cell activation, and up-regulation of four serum cytokines. This study provides insight into the immune responses to mRNA lipid nanoparticles, and suggests that pseudouridine modifications may be unnecessary for therapeutic application of mRNA in the liver.