Multi-modal effects of 1B3, a novel synthetic miR-193a-3p mimic, support strong potential for therapeutic intervention in oncology

Abstract

// Bryony J. Telford 1 , Sanaz Yahyanejad 1 , Thijs de Gunst 1 , Harm C. den Boer 1 , Rogier M. Vos 1 , Marieke Stegink 1 , Marion T.J. van den Bosch 1 , Mir Farshid Alemdehy 1 , Laurens A.H. van Pinxteren 1 , Roel Q.J. Schaapveld 1 and Michel Janicot 1 1 InteRNA Technologies BV, Utrecht, The Netherlands Correspondence to: Michel Janicot, email: janicot@interna-technologies.com Keywords: miR-193a-3p; microRNA mimic; microRNA delivery in vivo ; pleiotropic mechanism of microRNA; Received: October 16, 2020     Accepted: February 01, 2021     Published: March 02, 2021 Copyright: © 2021 Telford et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Compelling evidence demonstrates that miR-193a-3p is a tumor suppressor microRNA in many cancer types, and its reduced expression is linked to cancer initiation and progression, metastasis, and therapy resistance. However, its mechanism of action is not consistently described between studies, and often contradicts the pleiotropic role of a microRNA in manipulating several different mRNA targets. We therefore comprehensively investigated miRNA-193a-3p's mode of action in a panel of human cancer cell lines, with a variety of genetic backgrounds, using 1B3, a synthetic microRNA mimic. Interestingly, the exact mechanism through which 1B3 reduced cell proliferation varied between cell lines. 1B3 efficiently reduced target gene expression, leading to reduced cell proliferation/survival, cell cycle arrest, induction of apoptosis, increased cell senescence, DNA damage, and inhibition of migration. SiRNA silencing of 1B3 target mRNAs further highlighted the advantage of the pleiotropic mechanism of 1B3 action, as repression of individual targets did not achieve the same robust effect on cell proliferation in all cell lines. Importantly, a novel lipid nanoparticle-based formulation of 1B3, INT-1B3, demonstrated marked anti-tumor activity as a single agent following systemic administration in tumor-bearing mice. Together, these data strongly support the development of 1B3 as a novel therapeutic agent for treatment of human cancer.