Observation on efficacy, pharmacokinetic behaviors and safety of new modified RNA oligonucleotide targeting Foxo-1 via two routes of administration
10.16438/j.0513-4870.2019-0169
- VernacularTitle: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
- Author:
Zhuo YANG
1
;
Wen QIN
1
;
Jing-bo WANG
1
;
Li-yuan WANG
1
;
Qin ZHUO
1
;
Bo TIAN
2
Author Information
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
- Publication Type:Research Article
- Keywords:
Foxo-1;
antisense oligonucleotides;
efficacy;
pharmacokinetic behavior;
safety
- From:
Acta Pharmaceutica Sinica
2019;54(7):1251-1256
- CountryChina
- Language:Chinese
-
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.