Genotoxicity evaluation of self-assembled-micelle inhibitory RNA-targeting amphiregulin (SAMiRNA-AREG), a novel siRNA nanoparticle for the treatment of fibrotic disease

Abstract

The self-assembled-micelle inhibitory RNA-targeting amphiregulin (SAMiRNA-AREG) is a novel small-interfering RNA (siRNA) nanoparticle that is used for treatment of pulmonary fibrosis. We investigated the potential genotoxicity of SAMiRNA-AREG based on the guidelines published by the Organization for Economic Cooperation and Development. In the bacterial reverse mutation assay (Ames test), SAMiRNA-AREG did not induce mutations in Salmonella typhimurium TA100, TA1535, TA98, and TA1537 and Escherichia coli WP2uvrA at concentrations of up to 3000 μg/plate with or without metabolic activation. The SAMiRNA-AREG (concentrations up to 500 μg/mL) did not induce chromosomal aberrations in cultured Chinese hamster lung cells with or without metabolic activation. In the in vivo mouse bone marrow micronucleus assay, the SAMiRNA-AREG (concentrations up to 300 mg/kg body weight) did not affect the proportions of polychromatic erythrocytes and total erythrocytes, nor did it increase the number of micronucleated polychromatic erythrocytes in ICR mice. Collectively, these results suggest that SAMiRNA-AREG is safe with regard to genotoxicity such as mutagenesis or clastogenesis under the present experimental conditions. These results might support the safety of SAMiRNA-AREG as a potential therapeutic agent for pharmaceutical development.

Keywords:

• Self-assembled-micelle interfering RNA nanoparticle
• genotoxicity
• safety evaluation
• amphiregulin
• GLP study

Disclosure statement

The authors declare that there is not any conflict of interest.

Additional information

Funding

This research was supported by a grant funded by Civil and Military Dual-use Technology Program [14-CM-EB-09; NTIS 1695004819) and Korea Drug Development Fund (KDDF) funded by Ministry of Science, ICT, and Future Planning (MSIP); the Ministry of Trade, Industry, and Energy (MOTIE); the Ministry of Health and Welfare (MOHW) [Grant No KDDF-201706–03, Republic of Korea]. It was also supported by Bioneer Corporation and siRNAgen Therapeutics Research Fund.