Messenger RNA (mRNA) therapeutics delivered via lipid nanoparticles hold the potential to treat metabolic diseases caused by protein deficiency, including propionic acidemia (PA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). Herein we report results from multiple independent preclinical studies of mRNA-3927 (an investigational treatment for PA), mRNA-3705 (an investigational treatment for MMA), and mRNA-3210 (an investigational treatment for PKU) in murine models of each disease. All 3 mRNA therapeutics exhibited pharmacokinetic/pharmacodynamic (PK/PD) responses in their respective murine model by driving mRNA, protein, and/or protein activity responses, as well as by decreasing levels of the relevant biomarker(s) when compared to control-treated animals. These preclinical data were then used to develop translational PK/PD models, which were scaled allometrically to humans to predict starting doses for first-in-human clinical studies for each disease. The predicted first-in-human doses for mRNA-3927, mRNA-3705, and mRNA-3210 were determined to be 0.3, 0.1, and 0.4 mg/kg, respectively.

通过脂质纳米颗粒传递的信使 RNA (mRNA) 疗法具有治疗蛋白质缺乏引起的代谢疾病的潜力，包括丙酸血症 (PA)、甲基丙二酸血症 (MMA) 和苯丙酮尿症 (PKU)。在此，我们报告了 mRNA-3927（PA 的研究性治疗方法）、mRNA-3705（MMA 的研究性治疗方法）和 mRNA-3210（PKU 的研究性治疗方法）在每种疾病的小鼠模型中的多项独立临床前研究的结果。与对照相比，所有 3 种 mRNA 疗法通过驱动 mRNA、蛋白质和/或蛋白质活性反应，以及通过降低相关生物标志物的水平，在各自的小鼠模型中表现出药代动力学/药效 (PK/PD) 反应。治疗的动物。然后，这些临床前数据被用来开发转化 PK/PD 模型，该模型以异速生长的方式缩放到人体，以预测每种疾病的首次人体临床研究的起始剂量。 mRNA-3927、mRNA-3705 和 mRNA-3210 的预测首次人体剂量分别为 0.3、0.1 和 0.4 mg/kg。