Zhang Yu, Xi Xiaodong, Yu Hang, Yang Liuyan, Lin Jinzhong, Yang Wen, Liu Junling, Fan Xuemei, Xu Yingjie
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
Mol Ther Nucleic Acids. 2022 Aug 13;29:657-671. doi: 10.1016/j.omtn.2022.08.017. eCollection 2022 Sep 13.
The use of messenger RNA (mRNA) enables the transient production of therapeutic proteins with stable and predictable translational kinetics and without the risk of insertional mutagenesis. Recent findings highlight the enormous potential of mRNA-based therapeutics. Here, we describe the synthesis of chemically modified thrombopoietin (TPO) mRNA through transcription and delivery via lipid nanoparticles (LNPs). After delivery of TPO mRNA in mice, compared with normal physiological values, plasma TPO protein levels increased over 1000-fold in a dose-dependent manner. Moreover, through a single intravenous dose of TPO mRNA-loaded LNPs, both reticulated and total platelet count increased significantly in mice, demonstrating that TPO protein derived from the exogenous mRNA was able to maintain normal activity. Submicrogram quantity of N-methylpseudouridine-modified TPO mRNA showed a similar effect in promoting thrombopoiesis as that by the TPO receptor agonist romiplostim. In addition, a therapeutic value was established in anti-GPIbα (CD42b) antibody-induced thrombocytopenia mouse models that showed a fast recovery of platelet count. Our study demonstrated chemically modified -transcribed TPO mRNA as a potentially safe therapeutic intervention to stimulate thrombopoiesis.
信使核糖核酸（mRNA）的应用能够瞬时产生治疗性蛋白质，其翻译动力学稳定且可预测，并且不存在插入诱变的风险。最近的研究结果凸显了基于mRNA的疗法的巨大潜力。在此，我们描述了通过转录合成化学修饰的血小板生成素（TPO）mRNA，并通过脂质纳米颗粒（LNP）进行递送。在将TPO mRNA递送至小鼠体内后，与正常生理值相比，血浆TPO蛋白水平呈剂量依赖性增加了1000多倍。此外，通过单次静脉注射负载TPO mRNA的LNP，小鼠的网织血小板计数和总血小板计数均显著增加，表明源自外源性mRNA的TPO蛋白能够维持正常活性。亚微克量的N-甲基假尿苷修饰的TPO mRNA在促进血小板生成方面显示出与TPO受体激动剂罗米司亭类似的效果。此外，在抗糖蛋白Ibα（CD42b）抗体诱导的血小板减少症小鼠模型中确立了其治疗价值，该模型显示血小板计数快速恢复。我们的研究证明，化学修饰转录的TPO mRNA是一种刺激血小板生成的潜在安全治疗干预措施。
