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

Observation on efficacy, pharmacokinetic behaviors and safety of new modified RNA oligonucleotide targeting Foxo-1 via two routes of administration

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。

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 of30 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.