Page 54 - ITPS-7-3

INNOSC Theranostics

and Pharmacological Sciences

REVIEW ARTICLE
Criteria for developing active cellular targeting

miRNA oligonucleotide therapeutics with a
peptide nucleic acid backbone: Combating

cardiometabolic pandemics

Marc Thibonnier*
Aptamir Therapeutics, Inc., Naples, Florida, United States of America

Abstract
Oligonucleotide therapeutics (ONTs) represent a growing new class of therapeutic
agents aimed at addressing chronic diseases that remain untreatable by small
molecules and antibodies. Our goal was to establish a selection of several criteria
to design and develop miRNA-based ONTs, focusing on improved chemistry,
pharmacokinetics/pharmacodynamics (PK/PD) profiles, and safety characteristics
to combat cardiometabolic pandemics. By leveraging our own experimental data
obtained from experiments involving miR-22-3p antagomirs and a careful review of
the literature, we established a set of seven criteria to optimize the design of miRNA
ONTs. These criteria prioritize simplified drug synthesis, optimized PK/PD properties,
*Corresponding author: and reduced potential toxicities. This proposed set of seven criteria represents a novel
Marc Thibonnier
(mthibonnier@aptamir.com) strategy for developing active cellular targeting miRNA ONTs for various therapeutic
indications.
Citation: Thibonnier M. Criteria
for developing active cellular
targeting miRNA oligonucleotide
therapeutics with a peptide Keywords: MiRNAs; Antagomirs; Oligonucleotide therapeutics; Active cellular targeted
nucleic acid backbone: Combating delivery; Cardio-metabolic pandemics
cardiometabolic pandemics.
INNOSC Theranostics and
Pharmacological Sciences.
2024;7(3):3025.
doi: 10.36922/itps.3025 1. Introduction
Received: February 26, 2024 Twenty-five years after the initial discovery of RNA interference by Fire et al., innovations
1
Accepted: April 25, 2024 in RNA chemistry and delivery strategies have facilitated the design and advancement
of RNA-based therapies. Oligonucleotide therapeutics (ONTs) exhibit the ability
2-4
Published Online: July 16, 2024
to target almost any gene, including those associated with so-called “un-druggable
Copyright: © 2024 This diseases”—conditions where genes are implicated beyond the reach of small molecules
is an Open-Access article
5
distributed under the terms and antibodies. RNA-based ONTs are distinct from small molecules and protein drugs
of the Creative Commons in several aspects, particularly their mechanisms of action and clinical pharmacology
6
AttributionNoncommercial License, features. This distinction is especially notable in ONT conjugates designed for specific
permitting all non-commercial use,
distribution, and reproduction in any tissue delivery. 7,8
medium, provided the original work
is properly cited. The different classes and characteristics of ONTs currently being developed are
shown in Table 1.
Publisher’s Note: AccScience
Publishing remains neutral with Nineteen ONTs, mainly antisense oligonucleotides (ASOs) and small interfering
regard to jurisdictional claims in
published maps and institutional RNAs (siRNAs), have been approved by regulatory authorities for the treatment of
affiliations patients (Table 2). 9-12
Volume 7 Issue 3 (2024) 1 doi: 10.36922/itps.3025