Page 62 - ITPS-7-3

INNOSC Theranostics and
Pharmacological Sciences Designing miRNA ONTs for cardiometabolic pandemics

hepatocytes. Fifteen GalNAc3-conjugated 2’-MOE-
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modified ASOs are currently in clinical trials. Scientists
from Ionis Pharmaceutical compared the tolerability and
safety of four GalNAc3-conjugated and four identical
unconjugated 2’-MOE ASOs, demonstrating an enhanced
safety and tolerability of the GalNAc3-conjugated
compounds versus their unconjugated controls. They
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concluded that “the improved tolerability of the GalNAc3-
conjugated 2’MOE ASO likely reflects the use of reduced
doses and smaller sub-cutaneous injection volumes while
increasing the ASO potency.” 119,p24
The therapeutic utility of PNAs was initially hindered
by their own poor cellular permeability and the absence
of effective delivery strategies. However, recent advances
in PNA delivery using nanoparticles, ligands, and lipid
or peptide conjugates have improved their efficacy and
safety in vivo. 71,90,116,120-122 For instance, the South Korean
drug company OliPass is developing PNA compounds
for five different therapeutic indications using bases
containing cationic lipid groups to increase stability and Figure 4. Graphic representations of an 18 mer miR-22-3p antagomir
cell penetration. Effective therapeutic doses in animal with a PNA backbone coupled with a long chain fatty acid (C32:6
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studies were as low as 10 ng/kg, several orders of magnitude dotriacontahexaenoic acid) (A) and a hexapeptide (hexarelin) (B). Images
adapted from Thibonnier and Ghosh.
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lower than existing ASOs.
We opted to conjugate our miR-22-3p antagomir drug mRNA and protein expression levels of FAT across human
candidates to a fatty acid or a short peptide for enhanced tissues to those of the asialoglycoprotein receptor 1 used
targeted delivery to adipocytes and metabolic organs for the preferred delivery of ONTs to the liver (Figure 2).
through the cellular membrane transporter fatty acid This comparison underpins our rationale for targeting FAT
translocase (FAT). Our goal is to deliver a significantly for the preferred delivery of ONTs to metabolic organs.
reduced therapeutic dose to metabolic tissues and organs Examples of the structure and composition of AptamiR’s
of interest with an extended intracellular duration of action generation 2.5 active targeting miR-22-3p antagomirs are
(measured in mean residence time). shown in Figure 4.
We chose the cellular membrane transporter FAT
(FAT/CD36/SCARB3), which is the main route of 5. Discussion
uptake by adipose tissues of long-chain fatty acids as MiRNA-based ONTs could provide an effective and
well as short peptides, such as hexarelin, prohibitin, and convenient management of diseases, especially chronic
thrombospondin peptide-1. It is worth noting that FAT and prevalent ones. By shifting from the classical “one
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is present not only on the cell surface membrane but also drug-one target” strategy to a “one drug-many targets”
in intracellular compartments, notably the endosomes. paradigm, miRNA ONTs should produce significant
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Thus, the reversible translocation of FAT from endosomes therapeutic benefits while reducing polypharmacy, offering
to the plasma membrane facilitates fatty acid cellular substantial advantages in drug cost, efficacy, safety, and
uptake. patient compliance.
The membrane transporter FAT is present in cells Our work, along with others,’ has identified miR-
and tissues such as adipocytes, hepatocytes, skeletal and 22-3p as a promising candidate for the treatment
cardiac myocytes, pancreatic β-cells, kidney glomeruli of metabolic disorders associated with obesity and
and tubules cells, monocytes, and macrophages, which are metabolic dysfunction-associated steatotic liver disease
sensitive to metabolic dysfunctions (Figure 4). In an obese (MASLD). 53,54,56,61 We have established the efficacy of miR-
male patient weighing around 200 lbs with 40% adipose 22-3p antagomirs both in vitro in human cells in culture
tissue, there is a substantial quantity and density of FAT and in vivo preclinical animal models. The metabolic roles
available to transport our new generation 2.5 of miR- of miR-22 and the benefits of miR-22-3p antagomirs have
22-3p antagomirs coupled to a fatty acid or a peptide into been confirmed by several independent investigators,
the adipocytes. To illustrate this point, we compared the as summarized in a review paper by investigators at the

Volume 7 Issue 3 (2024) 9 doi: 10.36922/itps.3025