Safety pharmacology of self-assembled-micelle inhibitory RNA-targeting amphiregulin (SAMiRNA-AREG), a novel siRNA nanoparticle platform. (2021)

• Record Type: Journal Article
• Authors: Kim, Tae Rim; Kim, Hyeon-Young; Kim, In-Hyeon; Kim, Ki Cheon; Ko, Youngho; Park, Jun Hong; Yun, Sungil; Lee, In-Chul; Kim, Sung-Hwan; Park, Han-Oh
• Is Part Of: Toxicology reports. Volume 8(2021)
• Page Start: 839
• Page End: 845
• Publication Date: 2021
• Subjects: Self-assembled-micelle inhibitory RNA nanoparticle -- Amphiregulin -- Safety pharmacology -- Core battery; Toxicology -- Periodicals; Clinical toxicology -- Periodicals; Drug-Related Side Effects and Adverse Reactions; Hazardous Substances; Poisoning; Toxicology; Electronic journals; Periodicals; Periodicals; 571.9505
• DOI: 10.1016/j.toxrep.2021.03.022
• Languages: English
• ISSNs: 2214-7500

Abstract

Graphical abstract: Highlights: SAMiRNA-AREG is a modified siRNA nanoparticle for treatment of pulmonary fibrosis. Safety pharmacology of SAMiRNA-AREG was evaluated using core battery studies. No adverse effects on the neurobehavior, respiratory, and cardiovascular systems. These data provide important safety data for clinical trials in humans. Abstract: The present safety pharmacology core battery studies (neurobehavior, respiratory, cardiovascular system, and human ether a-go-go (hERG) channel current) investigated the potential harmful effects of self-assembled-micelle inhibitory RNA-targeting amphiregulin (SAMiRNA-AREG). The SAMiRNA-AREG was administered by single intravenous injection at up to 300 mg/kg and 100 mg/kg in mice and monkeys, respectively. The hERG assay was performed in Chinese hamster ovary (CHO) cells at SAMiRNA-AREG concentrations of up to 200 μg/mL. In the evaluation on neurobehavior, a transient decrease in body temperature was found at 0.5 h (30 min) post-dose at both sexes in mice, with a single 300 mg/kg dose of SAMiRNA-AREG. However, these effects had returned to normal at 1 h post-dose. In the evaluation on hERG channel current, there were statistically significant differences in the inhibition of peak hERG potassium channel current between the 20, 100, and 200 μg/mL SAMiRNA-AREG treatment groups and the vehicle control group. However, these effects were less potent than that of E-4031, a positive control article. For the respiratory and cardiovascular systems, no treatment-related changes were observed in mice or monkeys. Thus, under these experimental conditions, these studies suggest that SAMiRNA-AREG showed no adverse effects on the neurobehavior, respiratory, and cardiovascular function.