Morrissey, D. V. et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat. Biotechnol. 23, 1002–1007 (2005).
Zimmermann, T. S. et al. RNAi-mediated gene silencing in non-human primates. Nature 441, 111–114 (2006).
Frank-Kamenetsky, M. et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl Acad. Sci. USA 105, 11915–11920 (2008).
CAS PubMed PubMed Central Google Scholar
Akinc, A. et al. Development of lipidoid–siRNA formulations for systemic delivery to the liver. Mol. Ther. 17, 872–879 (2009).
CAS PubMed PubMed Central Google Scholar
Whitehead, K. A., Langer, R. & Anderson, D. G. Knocking down barriers: advances in siRNA delivery. Nat. Rev. Drug. Discov. 8, 129–138 (2009).
CAS PubMed PubMed Central Google Scholar
Tao, W. et al. Noninvasive imaging of lipid nanoparticle–mediated systemic delivery of small-interfering RNA to the liver. Mol. Ther. 18, 1657–1666 (2010).
CAS PubMed PubMed Central Google Scholar
Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28, 172–176 (2010).
Coelho, T. et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N. Engl. J. Med. 369, 819–829 (2013).
Hoy, S. M. Patisiran: first global approval. Drugs 78, 1625–1631 (2018).
Nair, J. K. et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 136, 16958–16961 (2014). This article reports the use of GalNAc conjugates for targeted delivery of siRNA to hepatocytes.
Zimmermann, T. S. et al. Clinical proof of concept for a novel hepatocyte-targeting GalNAc-siRNA conjugate. Mol. Ther. 25, 71–78 (2017).
CAS PubMed PubMed Central Google Scholar
Garber, K. Alnylam terminates revusiran program, stock plunges. Nat. Biotechnol. 34, 1213–1214 (2016).
Maraganore, J. Reflections on Alnylam. Nat. Biotechnol. 40, 641–650 (2022).
Egli, M. & Manoharan, M. Chemistry, structure and function of approved oligonucleotide therapeutics. Nucleic Acids Res. 51, 2529–2573 (2023). This article provides a comprehensive review on the chemistry and function of approved oligonucleotide-based drugs by early 2023.
CAS PubMed PubMed Central Google Scholar
Setten, R. L., Rossi, J. J. & Han, S.-P. The current state and future directions of RNAi-based therapeutics. Nat. Rev. Drug Discov. 18, 421–446 (2019). This review provides an excellent resource for understanding the basic biology of RNAi therapeutics.
Dowdy, S. F. Overcoming cellular barriers for RNA therapeutics. Nat. Biotechnol. 35, 222–229 (2017).
Dowdy, S. F., Setten, R. L., Cui, X.-S. & Jadhav, S. G. Delivery of RNA therapeutics: the great endosomal escape! Nucleic Acid. Ther. 32, 361–368 (2022). References 16 and 17 discuss the fundamental challenges of cellular uptake and endosomal escape of siRNAs.
CAS PubMed PubMed Central Google Scholar
Layzer, J. M. et al. In vivo activity of nuclease-resistant siRNAs. RNA 10, 766–771 (2004).
CAS PubMed PubMed Central Google Scholar
Gantier, M. P. & Williams, B. R. G. The response of mammalian cells to double-stranded RNA. Cytokine Growth Factor Rev. 18, 363–371 (2007).
CAS PubMed PubMed Central Google Scholar
Scacheri, P. C. et al. Short interfering RNAs can induce unexpected and divergent changes in the levels of untargeted proteins in mammalian cells. Proc. Natl Acad. Sci. USA 101, 1892–1897 (2004).
CAS PubMed PubMed Central Google Scholar
Khvorova, A. & Watts, J. K. The chemical evolution of oligonucleotide therapies of clinical utility. Nat. Biotechnol. 35, 238–248 (2017). This review discusses chemical modifications that evolve ASO and siRNA therapeutics towards clinical application.
CAS PubMed PubMed Central Google Scholar
De Smet, M. D., Meenken, C. & Van Den Horn, G. J. Fomivirsen—a phosphorothioate oligonucleotide for the treatment of CMV retinitis. Ocul. Immunol. Inflamm. 7, 189–198 (1999).
Kurreck, J. Antisense technologies. Improvement through novel chemical modifications. Eur. J. Biochem. 270, 1628–1644 (2003).
Lee, J.-H. et al. A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165. Proc. Natl Acad. Sci. USA 102, 18902–18907 (2005).
CAS PubMed PubMed Central Google Scholar
Brown, C. R. et al. Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates. Nucleic Acids Res. 48, 11827–11844 (2020).
CAS PubMed PubMed Central Google Scholar
Hassler, M. R. et al. Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo. Nucleic Acids Res. 46, 2185–2196 (2018). This article demonstrates that full chemical modification is essential for improving siRNA in vivo efficacy.
CAS PubMed PubMed Central Google Scholar
Allerson, C. R. et al. Fully 2′-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA. J. Med. Chem. 48, 901–904 (2005). This paper compares the potency of fully 2′-modified siRNA with unmodified siRNA.
Manoharan, M. et al. Unique gene-silencing and structural properties of 2′-fluoro-modified siRNAs. Angew. Chem. Int. Ed. 50, 2284–2288 (2011).
Jahns, H. et al. Stereochemical bias introduced during RNA synthesis modulates the activity of phosphorothioate siRNAs. Nat. Commun. 6, 6317 (2015).
Schirle, N. T., Sheu-Gruttadauria, J. & MacRae, I. J. Structural basis for microRNA targeting. Science 346, 608–613 (2014).
CAS PubMed PubMed Central Google Scholar
Manoharan, M. 2′-Carbohydrate modifications in antisense oligonucleotide therapy: importance of conformation, configuration and conjugation. Biochim. Biophys. Acta Gene Struct. Expr. 1489, 117–130 (1999).
Foster, D. J. et al. Advanced siRNA designs further improve in vivo performance of GalNAc-siRNA conjugates. Mol. Ther. 26, 708–717 (2018).
CAS PubMed PubMed Central Google Scholar
Blidner, R. A., Hammer, R. P., Lopez, M. J., Robinson, S. O. & Monroe, W. T. Fully 2′-deoxy-2′-fluoro substituted nucleic acids induce RNA interference in mammalian cell culture. Chem. Biol. Drug Des. 70, 113–122 (2007).
Janas, M. M. et al. Safety evaluation of 2′-deoxy-2′-fluoro nucleotides in GalNAc–siRNA conjugates. Nucleic Acids Res. 47, 3306–3320 (2019). This article investigates the safety of 2′-F nucleotides in GalNAc–siRNAs.
CAS PubMed PubMed Central Google Scholar
Schirle, N. T. & MacRae, I. J. The crystal structure of human argonaute2. Science 336, 1037–1040 (2012).
CAS PubMed PubMed Central Google Scholar
Davis, S. M. et al. Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1. Mol. Ther. Nucleic Acids 29, 135–149 (2022).
CAS PubMed PubMed Central Google Scholar
Grimm, D. et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441, 537–541 (2006).
Nair, J. K. et al. Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates. Nucleic Acids Res. 45, 10969–10977 (2017).
CAS PubMed PubMed Central Google Scholar
Judge, D. P. et al. Phase 3 multicenter study of revusiran in patients with hereditary transthyretin-mediated (hATTR) amyloidosis with cardiomyopathy (ENDEAVOUR). Cardiovasc. Drugs Ther. 34, 357–370 (2020).
CAS PubMed PubMed Central Google Scholar
Biscans, A. et al. The chemical structure and phosphorothioate content of hydrophobically modified siRNAs impact extrahepatic distribution and efficacy. Nucleic Acids Res. 48, 7665–7680 (2020).
CAS PubMed PubMed Central Google Scholar
Ly, S., Echeverria, D., Sousa, J. & Khvorova, A. Single-stranded phosphorothioated regions enhance cellular uptake of cholesterol-conjugated siRNA but not silencing efficacy. Mol. Ther. Nucleic Acids 21, 991–1005 (2020).
CAS PubMed PubMed Central Google Scholar
Wang, Y., Sheng, G., Juranek, S., Tuschl, T. & Patel, D. J. Structure of the guide-strand-containing argonaute silencing complex. Nature 456, 209–213 (2008).
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