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RNAi-based drug design: considerations and future directions

Nature Reviews Drug Discovery (2024)Cite this article

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Abstract

More than 25 years after its discovery, the post-transcriptional gene regulation mechanism termed RNAi is now transforming pharmaceutical development, proved by the recent FDA approval of multiple small interfering RNA (siRNA) drugs that target the liver. Synthetic siRNAs that trigger RNAi have the potential to specifically silence virtually any therapeutic target with unprecedented potency and durability. Bringing this innovative class of medicines to patients, however, has been riddled with substantial challenges, with delivery issues at the forefront. Several classes of siRNA drug are under clinical evaluation, but their utility in treating extrahepatic diseases remains limited, demanding continued innovation. In this Review, we discuss principal considerations and future directions in the design of therapeutic siRNAs, with a particular emphasis on chemistry, the application of informatics, delivery strategies and the importance of careful target selection, which together influence therapeutic success.

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Fig. 1: Mechanism of action of siRNA drugs.
Fig. 2: Medicinal chemistry of siRNA design.
Fig. 3: Strategies for altering pharmacokinetic profiles to improve siRNA systemic distribution and promote extrahepatic efficacy.
Fig. 4: Local delivery of siRNAs.
Fig. 5: Clinical indication and target selection for RNAi modulation.
Fig. 6: Promising future applications of siRNA drugs.

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Acknowledgements

The authors acknowledge the nucleic acid–medicine community who contributed to the technology innovations, and whose excellent work could not be included here owing to lack of space. This work was supported by the NIH (grant nos. R35 GM131839 and R01 NS104022 to A.K.; and K99 AR082987 to Q.T.). The authors thank M. B. Dziewietin for her administrative assistance and D. Conte at RNA Therapeutics Institute for help in revising and proofreading this manuscript.

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Authors and Affiliations

  1. RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA

    Qi Tang & Anastasia Khvorova

  2. Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, USA

    Qi Tang

  3. Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA

    Anastasia Khvorova

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  1. Qi Tang
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Correspondence to Anastasia Khvorova.

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Competing interests

A.K. is a founder of Atalanta Therapeutics and Comanche Biopharma; serves on the Scientific Advisory Board of Aldena Therapeutics, Prime Medicine, Alltrna, Advirna and Evox Therapeutics. A.K. and Q.T. are listed as inventors of RNAi technology patents and patent applications.

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Tang, Q., Khvorova, A. RNAi-based drug design: considerations and future directions. Nat Rev Drug Discov (2024). https://doi.org/10.1038/s41573-024-00912-9

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