药学学报, 2019, 54(7): 1251-1256
引用本文:
杨倬, 秦文, 王晶波, 王丽媛, 卓勤, 田波. 新型Foxo-1反义RNA两种给药方式的药效学、药动学和安全性观察[J]. 药学学报, 2019, 54(7): 1251-1256.
YANG Zhuo, QIN Wen, WANG Jing-bo, WANG Li-yuan, ZHUO Qin, TIAN Bo. Observation on efficacy, pharmacokinetic behaviors and safety of new modified RNA oligonucleotide targeting Foxo-1 via two routes of administration[J]. Acta Pharmaceutica Sinica, 2019, 54(7): 1251-1256.

新型Foxo-1反义RNA两种给药方式的药效学、药动学和安全性观察
杨倬1, 秦文1, 王晶波1, 王丽媛1, 卓勤1, 田波2
1. 中国疾病预防控制中心营养与健康所, 北京 100050;
2. 中国科学院微生物研究所病原微生物与免疫学重点实验室, 北京 100101
摘要:
Foxo-1(Forkhead box O1)在肌肉萎缩疾病的发生发展中起到了重要作用,有可能成为肌肉萎缩疾病治疗中潜在的治疗靶点。本研究设计了特异性靶向Foxo-1的2'-O-甲基和3'-丁醇基联合修饰的新型反义RNA寡核苷酸(oligos),并评价其在小鼠体内的药效学、药动学行为及安全性。所有实验方案均通过中国疾病预防控制中心营养与健康所动物伦理委员会批准。结果表明,不同剂量的RNA寡核苷酸通过静脉注射和口服给药均能降低小鼠骨骼肌Foxo-1的表达,有助于增加小鼠骨骼肌质量。药动学行为评价结果显示,新型修饰的Foxo-1 RNA寡核苷酸单次静脉注射给药后在小鼠体内的动力学过程符合二室模型。安全性评价结果显示,静脉注射或口服给药最高剂量为30 mg·kg-1的RNA寡核苷酸,小鼠的肝功能和肾功能以及血液学各项指标正常,未对小鼠产生明显的不良反应;并且未导致小鼠明显的组织病理变化。总之新型修饰的Foxo-1反义RNA寡核苷酸作用在小鼠体内是安全且有效的,为其临床应用提供了实验基础与指导意义。
关键词:    Foxo-1      反义RNA寡核苷酸      药效学      药动学行为      安全性     
Observation on efficacy, pharmacokinetic behaviors and safety of new modified RNA oligonucleotide targeting Foxo-1 via two routes of administration
YANG Zhuo1, QIN Wen1, WANG Jing-bo1, WANG Li-yuan1, ZHUO Qin1, TIAN Bo2
1. Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China;
2. Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Abstract:
Foxo-1 plays an important role in development of muscle atrophy, serving as a potential target for therapeutic treatment of the disease. In this study, the Foxo-1 mRNA was targeted by a Foxo-1 specific RNA oligonucleotide modified by 2'-O-methyl and with a butanol tag at the 3'-end. To understand the in vivo significance of new modified RNA oligos, efficacy, pharmacokinetic and safety profiles of the new modified RNA oligonucleotide targeting Foxo-1 were evaluated in mice. All experimental protocols were approved by the Animal Ethics Committee of Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention. The results showed that different doses of the RNA oligonucleotide can reduce the expression of Foxo-1 in mice by two routes of administration, leading to an increase in skeletal muscle mass of the mice. The results of pharmacokinetic evaluation showed that the plasma disappearance curve for the RNA oligonucleotide could be described by a two-compartmental model. The results of safety evaluation showed that no obvious adverse effects on renal and hepatic functions, nor on hematological parameters by intravenous or oral administration of the RNA oligo with a maximum dose of 30 mg·kg-1. Histopathology also did not reveal any significant changes in the morphology of the organs studied. In conclusion, the new modified RNA oligo is safe and effective in mice, providing experimental evidence supporting the significance for its clinical application.
Key words:    Foxo-1    antisense oligonucleotides    efficacy    pharmacokinetic behavior    safety   
收稿日期: 2019-03-11
DOI: 10.16438/j.0513-4870.2019-0169
通讯作者: 杨倬,Tel:86-10-66237243,E-mail:yangzhuo@ninh.chinacdc.cn
Email: yangzhuo@ninh.chinacdc.cn
相关功能
PDF(3177KB) Free
打印本文
0
作者相关文章
杨倬  在本刊中的所有文章
秦文  在本刊中的所有文章
王晶波  在本刊中的所有文章
王丽媛  在本刊中的所有文章
卓勤  在本刊中的所有文章
田波  在本刊中的所有文章

参考文献:
[1] Liu Y, Wang X, Leng W, et al. Aspartate inhibits LPS-induced MAFbx and MuRF1 expression in skeletal muscle in weaned pigs by regulating Akt, AMPKα and FOXO1[J]. Innate Immun, 2017, 23:34-43.
[2] Chacon Cabrera A, Fermoselle C, Urtreger AJ, et al. Pharmacological strategies in lung cancer-induced cachexia:effects on muscle proteolysis, autophagy, structure, and weakness[J]. J Cell Physiol, 2014, 229:1660-1672.
[3] Awad H, Nolette N, Hinton M, et al. AMPK and FoxO1 regulate catalase expression in hypoxic pulmonary arterial smooth muscle[J]. Pediatr Pulmonol, 2014, 49:885-897.
[4] Iannitti T, Morales Medina JC, Palmieri B. Phosphorothioate oligonucleotides:effectiveness and toxicity[J]. Curr Drug Targets, 2014, 15:663-673.
[5] Flierl U, Nero TL, Lim B, et al. Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators[J]. J Exp Med, 2015, 212:129-137.
[6] Banks WA. Measurement of phosphorothioate oligodeoxynucleotide antisense transport across the blood-brain barrier[J]. Methods Mol Biol, 2011, 789:337-342.
[7] Lee JJA, Maruyama R, Duddy W, et al. Identification of novel antisense-mediated exon skipping targets in DYSF for therapeutic treatment of dysferlinopathy[J]. Mol Ther Nucleic Acids, 2018, 13:596-604.
[8] Prakash TP, Yu J, Kinberger GA, et al. Evaluation of the effect of 2'-O-methyl, fluoro hexitol, bicyclo and morpholino nucleic acid modifications on potency of GalNAc conjugated antisense oligonucleotides in mice[J]. Bioorg Med Chem Lett, 2018, 28:3774-3779.
[9] Chery J, Petri A, Wagschal A, et al. Development of locked nucleic acid antisense oligonucleotides targeting Ebola viral proteins and host factor Niemann-Pick C1[J]. Nucleic Acid Ther, 2018, 28:273-284.
[10] Osawa T, Sawamura M, Wada F, et al. Synthesis, duplex-forming ability, enzymatic stability, and in vitro antisense potency of oligonucleotides including 2'-C,4'-C-ethyleneoxy-bridged thymidine derivatives[J]. Org Biomol Chem, 2017, 15:3955-3963.
[11] Liu CM, Yang Z, Liu CW, et al. Effect of RNA oligonucleotide targeting Foxo-1 on muscle growth in normal and cancer cachexia mice[J]. Cancer Gene Ther, 2007, 14:945-952.
[12] Liu CM, Yang Z, Liu CW, et al. Myostatin antisense RNA-mediated muscle growth in normal and cancer cachexia mice[J]. Gene Ther, 2008, 15:155-160.
[13] Javanbakht H, Mueller H, Walther J, et al. Liver-targeted anti-HBV single-stranded oligonucleotides with locked nucleic acid potently reduce HBV gene expression in vivo[J]. Mol Ther Nucleic Acids, 2018, 11:441-454.
[14] Harada T, Matsumoto S, Hirota S, et al. Chemically modified antisense oligonucleotide against ARL4C inhibits primary and metastatic liver tumor growth[J]. Mol Cancer Ther, 2019, 18:602-612.
[15] Le BT, Adams AM, Fletcher S, et al. Rational design of short locked nucleic acid-modified 2'-O-methyl antisense oligonucleotides for efficient exon-skipping in vitro[J]. Mol Ther Nucleic Acids, 2017, 9:155-161.
[16] Toonen LJA, Casaca-Carreira J, Pellisé-Tintoré M, et al. Intracerebroventricular administration of a 2'-O-methyl phosphorothioate antisense oligonucleotide results in activation of the innate immune system in mouse brain[J]. Nucleic Acid Ther, 2018, 28:63-73.
[17] Donner AJ, Bell TA, Greenlee S, et al. Characterization of the activity and distribution of a 2'-O-methoxyethyl-modified antisense oligonucleotide in models of acute and chronic kidney disease[J]. Nucleic Acid Ther, 2018, 28:297-306.
[18] Yamada K, Abe Y, Murase H, et al. Synthesis and properties of 2'-OMe-RNAs modified with cross-linkable 7-deazaguanosine derivatives[J]. J Org Chem, 2018, 83:8851-8862.
[19] Shen W, De Hoyos CL, Sun H, et al. Acute hepatotoxicity of 2' fluoro-modified 5-10-5 gapmer phosphorothioate oligonucleotides in mice correlates with intracellular protein binding and the loss of DBHS proteins[J]. Nucleic Acids Res, 2018, 46:2204-2217.
[20] Istrate A, Katolik A, Istrate A, et al. 2'β-Fluoro-tricyclo nucleic acids (2'F-tc-ANA):thermal duplex stability, structural studies, and RNase H activation[J]. Chemistry, 2017, 23:10310-10318.