RNA interference in the era of nucleic acid therapeutics

• Published in: Nature biotechnology Vol. 42; no. 3; pp. 394 - 405
• Main Authors: Jadhav, Vasant, Vaishnaw, Akshay, Fitzgerald, Kevin, Maier, Martin A
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.03.2024
• Subjects: Acetylgalactosamine; Acids; Biotechnology; Chemistry; Chronic conditions; Chronic illnesses; Design; Drug development; Drugs; Durability; Epigenetics; FDA approval; Gene expression; Interference; Lipids; Liver; MicroRNAs; N-Acetylgalactosamine; Nanoparticles; Nucleic acids; R&D; Regulatory approval; Research & development; Ribonucleic acid; RNA; RNA Interference; RNA polymerase; RNA, Small Interfering - genetics; RNA, Small Interfering - therapeutic use; RNA-mediated interference; siRNA
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/s41587-023-02105-y

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.