Trends in Pharmacological Sciences
OpinionThe potential of long noncoding RNA therapies
Section snippets
The potential of long noncoding RNAs
RNA therapies can deliver a genetic message into cells with the purpose of preventing or treating a disease. Whilst RNA therapies have been in development for decades, recent advances in delivery, immunogenicity (see Glossary), and manufacture have enabled their potential to be realised, most notably with the success of small RNA therapies and mRNA vaccines (Box 1). These advances have also potentiated the development of noncoding RNA (ncRNA) as a new class of therapy [1].
Over the past two
Long noncoding RNA expression
LncRNAs are a novel gene class that are not translated into proteins but instead function intrinsically as RNA molecules. The biogenesis of lncRNAs is similar to mRNAs. They are typically transcribed by RNA polymerase II, are longer than 200 nucleotides in length, and are often spliced into alternative isoforms post-transcriptionally capped with a 7-methyl guanosine at the 5′ termini and polyadenylated at the 3′ termini [3]. However, in addition to this primary pathway, lncRNAs can also be
Targeting long noncoding RNAs in disease
LncRNAs have been assigned increasing roles in diverse diseases, including diabetes, cardiac, and neurological disorders. These roles are best characterised in cancer, where lncRNAs contribute to tumour metastasis, immune escape, metabolism, and angiogenesis [30]. Given these roles, lncRNAs may constitute attractive drug targets due to their low and tissue-specific expression, which can be drugged at lower doses with fewer undesired off-target toxic effects. For example, the majority of
The therapeutic potential of long noncoding RNAs
The natural ability of lncRNAs to regulate cellular pathways underpins their potential as an effective drug. However, the large size of lncRNAs can make delivery challenging and activate an immune response. By isolating the relevant functional regions of lncRNAs, it may be possible to engineer smaller synthetic lncRNA ‘mimics’ that form an effective drug. For example, the delivery of the full-length NRON lncRNA successfully inhibits bone resorption in a mouse model of osteoporosis, but also
Long noncoding RNA therapy design
Due to its versatile structure, RNA has proven a useful substrate for engineering of programmable devices, including sensors, actuators, and transmitters, which have been widely developed for synthetic biology applications [52]. This includes RNA aptamers, ribozymes, as well as RNA sensors that detect environmental chemicals, small molecules, proteins, or other nucleic acids. Together, these RNA devices form a useful toolkit that can be assembled into more complex circuits [53].
Many synthetic
Concluding remarks and future perspectives
Advances in our understanding of lncRNA biology and RNA chemistry underpin the potential for lncRNA therapies. However, further research is required to realise this potential. Identifying the sequence and structural domains that transact the cellular functions of lncRNAs is needed for the programmable design of synthetic lncRNA therapies. However, given the diversity and abundance of lncRNAs, high-throughput computational and experimental approaches must be combined to identify functional
Declaration of interests
No interests are declared.
Glossary
- Chromatin
- the DNA, RNA, and protein, such as histones, that package the genome within the cell. Chromatin can be unwound or condensed to activate or silence gene expression, respectively.
- Gene dosage
- the number of copies of a gene that are present within a genome, and is often related to the abundance of the gene expression.
- Haploinsufficiency
- pathology caused when one copy of a gene is inactivated or deleted and the remaining gene copy does not produce sufficient gene product to preserve normal
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