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Page 175 Kamal et al. J Transl Genet Genom 2024;8:162-85 https://dx.doi.org/10.20517/jtgg.2023.55

progression of the disease. These microRNAs play a crucial role in the control of lipid homeostasis, and
their dysregulation has been linked to the development of fatty liver disease. RG-125, by modulating
miR-103/107 activity, has shown potential in preclinical studies to mitigate liver fat accumulation and
inflammation, offering a new avenue for the development of therapeutic interventions. The exploration of
RG-125 and its impact on miR-103/107 highlights the intricate molecular mechanisms involved in the
pathogenesis and underscores the potential of targeted therapies in addressing this increasingly prevalent
health concern .
[129]

MRX34
MRX34, a miR-34a mimic, represented an innovative approach in the field of RNA therapeutics by aiming
to supplement the tumor-suppressive functions of the microRNA known as miR-34a. MiR-34 plays a
pivotal role in regulating gene expression, particularly in the context of inhibiting cancer cell proliferation
and promoting apoptosis. The initial excitement surrounding MRX34 stemmed from its potential to mimic
the actions of miR-34a, thereby harnessing the natural mechanisms that control cellular processes and
suppress cancer development. However, the progress of clinical studies with MRX34 was abruptly halted
due to unforeseen severe immune-related adverse events observed in multiple patients. This unexpected
outcome raised concerns about the safety profile of the miR-34a mimic and underscored the challenges and
complexities associated with the development of RNA-based therapeutics in the quest for innovative cancer
treatments .
[130]

A summary of different types of RNA therapeutics and their related commercialized and in-development
drugs are shown in Figure 4 and Table 1, respectively.

CHALLENGES AND LIMITATIONS OF LncRNA THERAPEUTIC DEVELOPMENT
As of now, no lncRNA-based therapeutics have entered clinical trials in any phase. Despite this, the
promising potential of lncRNAs as a therapeutic approach suggests that their entry into clinical trials is on
the horizon [106,136] . Nevertheless, the development of lncRNA-based therapeutics must navigate challenges
and limitations to maximize therapeutic efficacy and ensure the successful translation of these innovative
approaches into clinical applications.

Cross-species sequence variation
The sequence variation in lncRNA sequences that is present between humans and animal models used for
experimentation can make it difficult to create effective therapeutics. Drugs found through testing on
human cells may not work when tested on rodents or other disease models, as lncRNAs may have different
functions in humans compared to other animals. To overcome this, animal models might have to be altered
to express the same lncRNA present in humans. However, this would be a difficult task as it would require a
thorough understanding of the lncRNA and its target gene interactions .
[137]
Optimum silencing strategy
Silencing genes can be used to study the function of a lncRNA through the use of antisense oligonucleotides
or double-stranded RNAs. However, silencing lncRNAs is more complex than silencing mRNA because the
subcellular localization of lncRNAs varies and different silencing strategies have varying effectiveness.
Antisense oligonucleotides are more effective in targeting RNAs located in the cell nucleus, while double-
stranded RNAs are better for RNAs in the cytoplasm. This suggests that if a target RNA is expected to
perform a role in the nucleus, antisense oligonucleotides would be the best silencing method, while double-
stranded RNAs would be better for targets thought to function in the cytoplasm [138,139] .