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Page 224 Bergara-Muguruza et al. J Transl Genet Genom 2023;7:213-229 https://dx.doi.org/10.20517/jtgg.2023.14

THE POTENTIAL THERAPEUTIC USE OF lncRNAs
Numerous lncRNAs affected by cancer-associated SNPs have been linked to drug resistance in cancer .
[14]
Therefore, potential future applications might be incorporating patients' non-coding genome sequence data
to significantly improve the selection of appropriate treatment strategies. Nonetheless, a thorough
understanding of the link between potential mutations in lncRNAs and the progression of disease or
[14]
resistance to drugs is still needed .
Studying the functional implication of SNPs within lncRNAs reveals diverse molecular mechanisms
associated with the progression of complex diseases, opening up new possibilities for targeted therapeutic
approaches. Lately, there has been a surge of interest in RNA-based treatments, particularly those focusing
[105]
on mRNA molecules, such as RNA vaccines . Moreover, the increasing studies relating lncRNAs in
diverse complex diseases such as autoimmune disorders have encouraged different research groups to study
the therapeutic use of these molecules. Recent clinical studies have opened possibilities for targeting these
lncRNAs for therapeutic purposes, emphasizing the importance of further research in this area.

lncRNAs possess characteristics that make them promising diagnostic tools. As they are involved in diverse
cellular processes and exhibit cell type-, tissue- and disease status-specific expression patterns, lncRNAs can
serve as diagnostic markers for specific diseases. Disease-specific expression levels of lncRNAs have been
described; hence, quantification of lncRNA can be used to detect disease presence even before symptoms
appear in some patients. Other lncRNAs can be related to disease prognosis or treatment resistance .
[16]
Interestingly, some lncRNAs have been detected in body fluids such as serum, plasma, or urine, so they can
be detected by non-invasive methods, making them attractive candidates as biomarkers for disease
diagnosis and prognosis. Additionally, enriched exosome lncRNA expression in plasma has also been
identified in esophageal squamous cell carcinoma patients, while circRNAs have also been enriched in
exosomes and showed potential diagnostic use .
[16]

lncRNA features also make them attractive drug targets, as lower doses would potentially minimize off-
target toxic effects . The most advanced attempts at therapeutic lncRNA targeting are currently based on
[105]
the use of antisense oligonucleotides (ASOs), which can form complementary base pairs with their target
lncRNAs . ASOs binding to target nascent lncRNAs within the nucleus results in premature transcription
[105]
[106]
termination, hence reducing lncRNA expression levels . Similarly, small interfering RNAs (siRNAs) can
trigger post-transcriptional RNA degradation, leading to the knockdown of pathogenic RNAs through a
dicer- and argonaute (AGO)-dependent cleavage pathway . Alternatively, lncRNA genes can be
[107]
modulated through steric blockade of their promoters or by utilizing genome-editing techniques such as
CRISPR-Cas9 and its derivatives .
[107]

Library screenings have already identified small molecules that are capable of specifically binding to
lncRNAs and inhibiting their interactions with other molecules. This strategy enhances the stability of the
target lncRNA, allowing it to carry out its functions effectively. This is the case of some of the lncRNAs
mentioned in this review, such as GAS5 and MALAT1 .
[109]
[108]
Rather than modulating their functions, the participation of lncRNAs in diverse cellular pathways
underscores their potential as effective therapeutic agents. For example, in order to activate or silence gene
expression, lncRNAs can be tethered to the nucleus, where they can regulate target gene expression.
Therefore, the design and delivery of lncRNAs to target specific gene loci could enable programmable gene
activation or silencing. However, the large size of lncRNAs can pose challenges for delivery and may trigger
an immune response. Identification of the functional regions of lncRNAs could facilitate the engineering of