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INNOSC Theranostics and
Pharmacological Sciences Designing miRNA ONTs for cardiometabolic pandemics

University of California, Davis, United States. Early 2035, nearly 3% of current global gross domestic product.”
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clinical trials for miR-22-3p antagomirs should be initiated MASLD affects 25% of the global adult population, and the
in the near future. prevalence of liver steatosis is 76% in obese patients. At
Relying on an extensive and critical review of the present, there is no FDA-approved medication for MASLD
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literature and our own experience, we selected a set of treatment. Obesity and MASLD are growing and costly
seven criteria based on scientific parameters, PK/PD pandemics in need of safe, effective, convenient, and
profile, ease, and cost of development to design generation affordable therapies.
2.5 miRNA ONTs. Once the target miRNA of interest Ten years ago, there was little “appetite” to invest in new
is selected according to criterion 1, five other criteria drugs for obesity and related cardiometabolic disorders
(criterions 2 – 6) can be simultaneously addressed by due to limited efficacy and serious adverse events leading
selecting a modified PNA backbone. The critical criterion to drug non-approval or even removal from the market.
7, which involves enhanced selective delivery to the tissues Regulatory authorities required long and costly outcome
and organs of interest, can be satisfied by coupling the PNA studies, causing large pharmaceutical companies to shy away
antagomir to a fatty acid or peptide actively transported by from this market. However, 10 years later, the landscape
a cellular membrane transporter expressed in the tissue/ has changed significantly, thanks to the development of
organ of interest. Therefore, the modified PNA with its new classes of agents, especially single, double, and triple
targeting moiety can achieve all these criteria (reduced incretins agonists for obesity and diabetes mellitus, and
potential toxicity, chemical stability, no chirality, superior thyroid hormone receptor β agonists for MAFLD. 134,135 In a
PK/PD profile, ease, and cost of synthesis). This set of phase II clinical trial, the triple-hormone receptor agonist
criteria could be applied to the development of miRNA retatrutide achieved up to 24% weight reduction at 48 weeks,
ONTs for various therapeutic indications. comparable to metabolic/bariatric surgery outcomes. In
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In the case of specific organs or tissues, such as the MAESTRO-NAFLD-1 52-week randomized, double-
the eyes, the brain, and the lungs, the mode and type blind, placebo-controlled phase III trial in adults with
of local administration represent another targeted NAFLD, the thyroid hormone receptor beta-selective
delivery option. Several ONTs approved for ocular agonist resmetirom was safe and well tolerated. Data
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diseases (cytomegalovirus retinitis and age-related from a phase III randomized controlled trial revealed
macular degeneration) are delivered through intravitreal resolution of NASH and/or fibrosis improvement after
administration (Table 1). Various ONT formulations 52 weeks of treatment with resmetirom. 138,139
directly delivered to the lungs using aerosolized inhalers Treatment selection for combating chronic cardio-
for the treatment of fibrotic lung diseases, as well as asthma metabolic pandemics should rely on efficacy, safety,
and lung cancer, are currently in clinical trials and display convenience, and cost/affordability parameters. The details
few systemic side effects. 127
are further elaborated as follows:
The clinical relevance of ONTs in the context of cardio- (i) Efficacy: Incretins and metabolic/bariatric surgery
metabolic pandemics can now be addressed by the example have now set the bar for body weight reduction in
of inclisiran, the first-in-class siRNA targeting PCSK9 human subjects at the -24% level that new drug
approved by both the US Food and Drug Administration candidates should meet
(FDA) and European Medicines Evaluation Agency. (ii) Safety and tolerability: Several years of pre- and
Inclisiran is an effective and convenient way to tackle post-approval monitoring are required to accurately
the huge burden of dyslipidemia and atherosclerotic identify the type and incidence of potential adverse
cardiovascular disease. The ORION/VICTORIAN events of a given drug. 140
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clinical trials have shown that inclisiran is both safe and (iii) Convenience and compliance: Twice-a-year
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efficient for up to 5 years. Ongoing animal and human subcutaneous administration of the siRNA inclisiran
studies are testing ASO, siRNA, and miRNA compounds to (Leqvio ) demonstrates improved adherence to
®
treat metabolic syndrome, which afflicts a large percentage therapy and lower low-density lipoprotein cholesterol
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of the world population. Recently, Nappi et al. reviewed over time, which in turn is postulated to improve
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the roles of miRNAs in the cardiovascular system, focusing clinical outcomes. 141-143 Such benefits should
on clinical translation. apply to targeting ONTs developed for combating
Obesity affects one-third of the world’s population, cardiometabolic pandemics.
including millions of children. This report suggests that (iv) Cost/affordability: Chronic cardiometabolic pandemics
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“on current trends, overweight and obesity will cost the affect a large fraction of the world’s population. As far as
global economy over US$4 trillion of potential income in ONTs are concerned, there is relevant experience with

Volume 7 Issue 3 (2024) 10 doi: 10.36922/itps.3025