Opinion
The potential of long noncoding RNA therapies

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Highlights

  • Advances in long noncoding RNA (lncRNA) biology have identified sequence motifs and secondary structures that bind DNA, RNA, or protein targets. An understanding of these structures and their function is needed for the rational and programmable design of lncRNA therapies.

  • LncRNAs contribute to diverse disease aetiologies and may be targeted using small molecules and antisense oligonucleotides.

  • Advances in RNA chemistry, including sequence optimisation and nucleotide modifications, have improved the stability and reduced the immunogenicity of RNA therapies.

  • Formulation of RNA therapies with delivery vehicles, such as lipid nanoparticles, improves stability and enables delivery to target cells and tissues at sufficient dosage.

  • Cellular reprogramming using synthetic mRNAs has demonstrated the ability to modulate gene expression and affect cellular phenotype.

  • Studies have demonstrated the effectiveness of synthetic lncRNA therapies in treating animal disease models.

The human genome expresses vast numbers of long noncoding RNAs (lncRNA) that fulfil diverse roles in gene regulation, cell biology, development, and human disease. These roles are often mediated by sequence motifs and secondary structures bound by proteins and can regulate epigenetic, transcriptional, and translational pathways. These functional domains can be further optimised and engineered into RNA devices that are widely used in synthetic biology. We propose that natural lncRNA structures can be explored and exploited for the rational design and assembly of synthetic RNA therapies. This potential has been enabled by advances in the stability, immunogenicity, manufacture, and delivery of other RNA-based therapies, from which we can anticipate the pharmacological properties of lncRNA therapies that have not yet otherwise entered clinical trials.

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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