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INNOSC Theranostics and
Pharmacological Sciences Designing miRNA ONTs for cardiometabolic pandemics

Table 5. Checklist to develop an oligonucleotide therapeutic Compared to other therapeutic classes, ONTs are
reasonably easy to synthesize with high purity at a
Step Task competitive cost. 147,148 The new generation 2.5 ONTs
1 Choose a relevant disease or unmet medical need allow the convenient administration of reduced doses
2 Select a specific RNA target and related on an extended schedule (e.g., bi-annual for inclisiran
network of genes and proteins [Leqvio]), which should reduce costs and improve
3 Elect an ONT type (ASO, dsRNA, miRNA patients’ compliance with treatment.
agomir or antagomir, aptamer)
4 Incorporate chemical modifications for Using the example of miR-22-3p as a therapeutic target,
achieving optimized drug-like properties we propose a set of seven criteria to optimize the design
5 Pick a targeting agent/delivery method to and PK/PD profile of active cellular targeting miRNA
achieve the best PK/PD profile ONTs. These criteria could be easily adapted to other
6 Validate lead candidate with machine miRNA targets and human diseases, especially chronic and
learning, in vitro, and in vivo studies endemic ones.
7 Optimize and simplify the chemical synthesis Obviously, the validity of such modifications must be
of the lead candidate to reduce costs confirmed by testing the lead candidate in animal models
Abbreviation: PK/PD: Pharmacokinetic/pharmacodynamics. and, eventually, human subjects.

inclisiran. At the publicly available price of $3,250 Acknowledgments
144
per dose, Leqvio was found to have “an incremental We would like to thank Pr. Pengyu Ren and his team,
®
cost-effectiveness ratio (ICER) just above the $50,000 Department of Biomedical Engineering at UT Austin, for
per quality-adjusted life year threshold of $51,686.” By performing the in silico modeling of our ONTs using high-
comparison, the ICER of the dual GLP-1/GIP analog performance molecular dynamics modeling on graphics
®
Tirzepatide is $70,147 for the 10 mg dose and $54,699 processing units.
for the 15 mg dose versus the GLP-1 analog semiglutide
2 mg as recently reported in patients with Type 2 Funding
diabetes mellitus in the US. In US adult patients This research received no external funding. Funding for
145
with overweight and obesity, semaglutide 2.4 mg was this R and D work was provided by AptamiR Therapeutics,
also estimated to be cost-effective compared with no Inc.
treatment and other anti-obesity medications, with
ICERs ranging from $27,113 (vs. no treatment) to Conflict of interest
$144,296 (vs. phentermine-topiramate). 146
Marc Thibonnier is the founder and a shareholder of
Thus, an active cellular targeting miRNA antagomir AptamiR Therapeutics, Inc.
with a PNA backbone produced by solid phase synthesis
and a bi-annual administration regimen should be cost- Author contributions
effective, an assumption that will need to be confirmed by This is a single-authored article.
clinical studies and cost-effectiveness analyses.
Ethics approval and consent to participate
6. Conclusion
Not applicable.
ONTs represent a new class of potent therapeutic agents
that are now achieving regulatory approvals for use in Consent for publication
humans. Within a few years, they have evolved from Not applicable.
treating a specific disease of the eyes, muscles, or brain
to addressing cardiometabolic pandemics (e.g., inclisiran Availability of data
[Leqvio] for elevated cholesterol and zilebesiran for
arterial hypertension). These developments are the results Data presented in this article can be accessed in our
or by request to the
previously published work
53,54,56
of improvements in nucleic acid chemical modifications, corresponding author.
conjugation to targeting ligands, and/or combination with
delivery systems. References
The road map to the successful development of an ONT 1. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE,
is summarized in Table 5. Mello CC. Potent and specific genetic interference by

Volume 7 Issue 3 (2024) 11 doi: 10.36922/itps.3025