Abstract
Two decades of research on RNA interference (RNAi) have transformed a breakthrough discovery in biology into a robust platform for a new class of medicines that modulate mRNA expression. Here we provide an overview of the trajectory of small-interfering RNA (siRNA) drug development, including the first approval in 2018 of a liver-targeted siRNA interference (RNAi) therapeutic in lipid nanoparticles and subsequent approvals of five more RNAi drugs, which used metabolically stable siRNAs combined with N-acetylgalactosamine ligands for conjugate-based liver delivery. We also consider the remaining challenges in the field, such as delivery to muscle, brain and other extrahepatic organs. Today’s RNAi therapeutics exhibit high specificity, potency and durability, and are transitioning from applications in rare diseases to widespread, chronic conditions.
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We thank the many contributors at Alnylam and other colleagues in the field who have contributed to the advancement of oligonucleotide therapeutics over the past several decades. We offer special thanks to T. Auperin for his tremendous support during the writing and editing of this manuscript. We also acknowledge the medical writing services provided by E. Childs and colleagues of Adelphi Communications (Macclesfield, UK), in accordance with Good Publication Practice guidelines, funded by Alnylam Pharmaceuticals.
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Jadhav, V., Vaishnaw, A., Fitzgerald, K. et al. RNA interference in the era of nucleic acid therapeutics. Nat Biotechnol 42, 394–405 (2024). https://doi.org/10.1038/s41587-023-02105-y
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DOI: https://doi.org/10.1038/s41587-023-02105-y
