Chemically modified in-vitro-transcribed mRNA encoding thrombopoietin stimulates thrombopoiesis in mice.
Chemically modified in-vitro-transcribed mRNA encoding thrombopoietin stimulates thrombopoiesis in mice.
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DOI：
10.1016/j.omtn.2022.08.017
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发表时间：
2022-09-13
期刊：
影响因子：
--
通讯作者：
Xu, Yingjie
中科院分区：
文献类型：
--
作者：
Zhang, Yu;Xi, Xiaodong;Yu, Hang;Yang, Liuyan;Lin, Jinzhong;Yang, Wen;Liu, Junling;Fan, Xuemei;Xu, Yingjie
信使RNA(信使RNA)的使用使治疗性蛋白质的瞬时产生具有稳定和可预测的翻译动力学，并且没有插入突变的风险。最近的发现突显了基于信使核糖核酸的疗法的巨大潜力。在这里，我们描述了通过体外转录和体内脂质纳米粒(LNPs)传递合成化学修饰的血小板生成素(TPO)mRNA。小鼠体内注射TPO基因后，血浆TPO蛋白水平较正常生理值升高1000倍以上，呈剂量依赖关系。此外，通过单次静脉注射TPO mRNA负载的LNPs，小鼠的网状和总血小板计数均显著增加，表明外源mRNA来源的TPO蛋白能够维持正常的活性。亚微克量的N1-甲基假尿苷修饰的TPO mRNA显示出与TPO受体激动剂罗米普替姆相似的促血小板生成作用。此外，在抗GPIBα(CD42b)抗体诱导的血小板减少小鼠模型中显示出血小板计数迅速恢复的治疗价值。我们的研究表明，化学修饰的体外转录的TPO mRNA是一种潜在的安全的治疗干预措施，可以刺激血小板生成。在正常和血小板减少的小鼠模型中，通过脂质纳米粒注射体外转录的血小板生成素(TPO)mRNA可以诱导TPO的产生并增加血小板数量。
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 in vitro transcription and in vivo 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 N1-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 in-vitro-transcribed TPO mRNA as a potentially safe therapeutic intervention to stimulate thrombopoiesis. Administration of in-vitro-transcribed thrombopoietin (TPO) mRNA by lipid nanoparticles induced TPO production and increased platelet counts in both normal and thrombocytopenia mouse models.
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影响因子：
12.4
作者：
Kariko, Katalin;Muramatsu, Hiromi;Welsh, Frank A.;Ludwig, Janos;Kato, Hiroki;Akira, Shizuo;Weissman, Drew
通讯作者：
Weissman, Drew
影响因子：
62.1
作者：
Kamaly N;Yameen B;Wu J;Farokhzad OC
通讯作者：
Farokhzad OC
影响因子：
158.5
作者：
Kuter, David J.;Rummel, Mathias;Berger, Dietmar P.
通讯作者：
Berger, Dietmar P.
影响因子：
158.5
作者：
Fanucchi, M;Glaspy, J;Harker, L
通讯作者：
Harker, L
影响因子：
10.8
作者：
Kauffman, Kevin J.;Dorkin, J. Robert;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.