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  • Review Article
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Targeting and engineering long non-coding RNAs for cancer therapy

Abstract

RNA therapeutics (RNATx) aim to treat diseases, including cancer, by targeting or employing RNA molecules for therapeutic purposes. Amongst the most promising targets are long non-coding RNAs (lncRNAs), which regulate oncogenic molecular networks in a cell type-restricted manner. lncRNAs are distinct from protein-coding genes in important ways that increase their therapeutic potential yet also present hurdles to conventional clinical development. Advances in genome editing, oligonucleotide chemistry, multi-omics and RNA engineering are paving the way for efficient and cost-effective lncRNA-focused drug discovery pipelines. In this Review, we present the emerging field of lncRNA therapeutics for oncology, with emphasis on the unique strengths and challenges of lncRNAs within the broader RNATx framework. We outline the necessary steps for lncRNA therapeutics to deliver effective, durable, tolerable and personalized treatments for cancer.

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Fig. 1: The genomic features and molecular mechanisms of lncRNAs.
Fig. 2: lncRNAs control cancer hallmarks by acting as tumour suppressors or oncogenes.
Fig. 3: Discovery tools for therapeutic lncRNAs.
Fig. 4: Pharmaceutical strategies for targeting lncRNAs.
Fig. 5: Current challenges with ASOs.
Fig. 6: Engineering lncRNA elements.

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Acknowledgements

Work in the Johnson laboratory is funded by Science Foundation Ireland through Future Research Leaders award 18/FRL/6194 and by the Irish Research Council through Consolidator Laureate award (IRCLA/2022/2500). M.C. acknowledges the support of DevelopMed, which received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 945425. The authors thank S. Ramnarayanan, T. Uroda and D. Harvey for helpful comments.

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R.J. is a paid consultant for NextRNA and inventor of the patent ‘Nucleic acid agents for treatment of non-small-cell lung cancer’ (WO2023061888A1). S.O. is CEO, founder and shareholder of HAYA Therapeutics SA. The other authors declare no competing interests.

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Coan, M., Haefliger, S., Ounzain, S. et al. Targeting and engineering long non-coding RNAs for cancer therapy. Nat Rev Genet 25, 578–595 (2024). https://doi.org/10.1038/s41576-024-00693-2

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