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Page 171 Kamal et al. J Transl Genet Genom 2024;8:162-85 https://dx.doi.org/10.20517/jtgg.2023.55

regulatory mediators resulted in the downregulation of the lncRNA HOTAIR and its action on inducing
[103]
breast cancer metastasis .
Cardiovascular disease
The potential therapeutic impact of lncRNAs in cardiovascular disease has been substantiated in numerous
research studies. For instance, in a study conducted by Li et al., a loss-of-function silencing assay was
performed on the dysregulated lncRNA RP11-544D21.2, which was identified to be upregulated in CHF
model cells. The findings revealed that the silencing of RP11-544D21.2 had a significant impact on various
downstream pathways, including the arrhythmogenic right ventricular cardiomyopathy pathway,
hypertrophic cardiomyopathy, antigen processing and presenting pathway, cell adhesion pathway-related
[85]
genes, cell cycle, focal adhesion, and Extracellular Matrix (ECM)-receptor interaction . Remarkably,
lncRNA ZNF593-AS was also discovered to alleviate contractile dysfunction not only in dilated
cardiomyopathy but also in diabetic cardiomyopathy [87,88] . These findings provide additional evidence for the
potential therapeutic benefits of lncRNAs in the context of cardiovascular disease.

RNAs IN DRUG DEVELOPMENT
Recently, researchers have begun to target RNAs as potential drug targets because they make up a large
portion of the genome and offer greater specificity than proteins. LncRNAs, in particular, may be a more
precise target than epigenetic complexes. RNA-based therapies also have the advantage of being highly
specific and stable . RNA-based drugs fall into the category of oligonucleotide-based drugs, which can be
[14]
classified into two main categories based on their chemical structure: double-stranded RNA drugs, such as
siRNA, and single-stranded DNA drugs . RNA molecules, such as antisense oligonucleotides, siRNAs,
[104]
microRNAs, and lncRNAs, may target mRNAs and ncRNAs with specificity through Watson-Crick base-
pairing. Antisense oligonucleotides, being the most common, have two different mechanisms of action:
RNA interference (RNAi) and RNase-H-mediated degradation .
[105]

Antisense oligonucleotides
Antisense oligonucleotides (ASOs) are unpaired DNA strands that have complete complementarity for a
single target mRNA molecule . The targeting of mRNAs or microRNAs through the use of ASOs results
[106]
in the degradation of the target through the activity of the RNase H endonuclease enzyme. This process
leaves the ASOs intact, allowing them to act as catalysts in the reaction and affect multiple target
molecules . These ASO-based drugs work by influencing the production or function of disease-causing
[107]
proteins through changes in pre-mRNA splicing, mRNA degradation, regulation of protein translation, or
direct interactions with proteins . ASOs need to be administered repeatedly because the oligonucleotides
[108]
are broken down by the cellular nucleases over time .
[109]

MicroRNAs
MicroRNAs are a class of ncRNAs that are small in size and capable of regulating the process of gene
expression of protein-coding genes post-transcription. They exist naturally, with over 2,300 different
microRNAs present in human cells, whose expression patterns differ depending on the tissue and time .
[110]
They form an imperfect RNA-hairpin structure due to regions of complementarity. When processed by the
RNA interference machinery, they create a 19-25 nucleotide RNA duplex with mismatching regions.
microRNAs normally bind to the 3' untranslated region (3' UTR) of mRNA and prevent protein translation.
Unlike siRNAs, which require virtually full sequence complementarity to cause cleavage of the target RNA,
microRNAs only need a small number of complementary nucleotides to the target mRNA in order to
inhibit its translation; therefore, microRNAs can have several targets throughout the cell . microRNAs
[109]
can be used as potential therapeutic approaches, as follows.