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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References
Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).
Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).
Statello, L., Guo, C.-J., Chen, L.-L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22, 96–118 (2021).
Ozata, D. M., Gainetdinov, I., Zoch, A., O’Carroll, D. & Zamore, P. D. PIWI-interacting RNAs: small RNAs with big functions. Nat. Rev. Genet. 20, 89–108 (2019).
Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64–71 (2008).
Obbard, D. J., Gordon, K. H., Buck, A. H. & Jiggins, F. M. The evolution of RNAi as a defence against viruses and transposable elements. Philos. Trans. R. Soc. Lond. B Biol. Sci. 364, 99–115 (2009).
Crooke, S. T., Witztum, J. L., Bennett, C. F. & Baker, B. F. RNA-targeted therapeutics. Cell Metab. 27, 714–739 (2018).
Dominski, Z. & Kole, R. Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proc. Natl Acad. Sci. USA 90, 8673–8677 (1993).
Gregory, R. I. et al. Human RISC couples MicroRNA biogenesis and posttranscriptional gene silencing. Cell 123, 631–640 (2005).
Zamore, P. D., Tuschl, T., Sharp, P. A. & Bartel, D. P. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101, 25–33 (2000).
Hammond, S. M., Bernstein, E., Beach, D. & Hannon, G. J. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature 404, 293–296 (2000).
Roberts, T. C. The microRNA machinery. Adv. Exp. Med. Biol. 887, 15–30 (2015).
Guo, H., Ingolia, N. T., Weissman, J. S. & Bartel, D. P. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835–840 (2010).
Eichhorn, S. W. et al. mRNA destabilization is the dominant effect of mammalian microRNAs by the time substantial repression ensues. Mol. Cell 56, 104–115 (2014).
Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004).
Haley, B. & Zamore, P. D. Kinetic analysis of the RNAi enzyme complex. Nat. Struct. Mol. Biol. 11, 599–606 (2004).
Brown, C. R. et al. Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates. Nucleic Acids Res. 48, 11827–11844 (2020).
Paunovska, K., Loughrey, D. & Dahlman, J. E. Drug delivery systems for RNA therapeutics. Nat. Rev. Genet. 23, 265–280 (2022).
Whitehead, K. A., Langer, R. & Anderson, D. G. Knocking down barriers: advances in siRNA delivery. Nat. Rev. Drug Discov. 8, 129–138 (2009).
Bowie, A. G. & Unterholzner, L. Viral evasion and subversion of pattern-recognition receptor signalling. Nat. Rev. Immunol. 8, 911–922 (2008).
Bumcrot, D., Manoharan, M., Koteliansky, V. & Sah, D. W. RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat. Chem. Biol. 2, 711–719 (2006).
Titze-de-Almeida, R., David, C. & Titze-de-Almeida, S. S. The race of 10 synthetic RNAi-based drugs to the pharmaceutical market. Pharm. Res. 34, 1339–1363 (2017).
Garba, A. O. & Mousa, S. A. Bevasiranib for the treatment of wet, age-related macular degeneration. Ophthalmol. Eye Dis. 2, 75–83 (2010).
Eisenstein, M. Pharma’s roller-coaster relationship with RNA therapies. Nature 574, S4–S6 (2019).
Bailey, A. L. & Cullis, P. R. Modulation of membrane fusion by asymmetric transbilayer distributions of amino lipids. Biochemistry 33, 12573–12580 (1994).
Semple, S. C. et al. Efficient encapsulation of antisense oligonucleotides in lipid vesicles using ionizable aminolipids: formation of novel small multilamellar vesicle structures. Biochim. Biophys. Acta 1510, 152–166 (2001).
Hafez, I. M., Maurer, N. & Cullis, P. R. On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids. Gene Ther. 8, 1188–1196 (2001).
Zimmermann, T. S. et al. RNAi-mediated gene silencing in non-human primates. Nature 441, 111–114 (2006).
Judge, A. D., Bola, G., Lee, A. C. & MacLachlan, I. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol. Ther. 13, 494–505 (2006).
Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28, 172–176 (2010).
Akinc, A. et al. Development of lipidoid–siRNA formulations for systemic delivery to the liver. Mol. Ther. 17, 872–879 (2009).
Love, K. T. et al. Lipid-like materials for low-dose, in vivo gene silencing. Proc. Natl Acad. Sci. USA 107, 1864–1869 (2010).
Akinc, A. et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18, 1357–1364 (2010).
Jayaraman, M. et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. Int. Ed. Engl. 51, 8529–8533 (2012).
Cullis, P. R. & Hope, M. J. Lipid nanoparticle systems for enabling gene therapies. Mol. Ther. 25, 1467–1475 (2017).
Fitzgerald, K. et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 383, 60–68 (2014).
Coelho, T. et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N. Engl. J. Med. 369, 819–829 (2013).
Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21 (2018).
Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1074–1094 (2021).
Szabó, G. T., Mahiny, A. J. & Vlatkovic, I. COVID-19 mRNA vaccines: platforms and current developments. Mol. Ther. 30, 1850–1868 (2022).
Maier, M. A. et al. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol. Ther. 21, 1570–1578 (2013).
Sabnis, S. et al. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates. Mol. Ther. 26, 1509–1519 (2018).
Zhang, X. et al. Biodegradable amino-ester nanomaterials for Cas9 mRNA delivery in vitro and in vivo. ACS Appl. Mater. Interfaces 9, 25481–25487 (2017).
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).
Morrissey, D. V. et al. Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication. Hepatology 41, 1349–1356 (2005).
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).
Butler, J. S. et al. Preclinical evaluation of RNAi as a treatment for transthyretin-mediated amyloidosis. Amyloid 23, 109–118 (2016).
Stockert, R. J., Morell, A. G. & Scheinberg, I. H. Mammalian hepatic lectin. Science 186, 365–366 (1974).
Steer, C. J. & Ashwell, G. Studies on a mammalian hepatic binding protein specific for asialoglycoproteins. Evidence for receptor recycling in isolated rat hepatocytes. J. Biol. Chem. 255, 3008–3013 (1980).
Stockert, R. J. et al. Endocytosis of asialoglycoprotein-enzyme conjugates by hepatocytes. Lab Invest. 43, 556–563 (1980).
Schwartz, A. L., Fridovich, S. E. & Lodish, H. F. Kinetics of internalization and recycling of the asialoglycoprotein receptor in a hepatoma cell line. J. Biol. Chem. 257, 4230–4237 (1982).
Rensen, P. C., van Leeuwen, S. H., Sliedregt, L. A., van Berkel, T. J. & Biessen, E. A. Design and synthesis of novel N-acetylgalactosamine-terminated glycolipids for targeting of lipoproteins to the hepatic asialoglycoprotein receptor. J. Med. Chem. 47, 5798–5808 (2004).
Huang, X., Leroux, J. C. & Castagner, B. Well-defined multivalent ligands for hepatocytes targeting via asialoglycoprotein receptor. Bioconjug. Chem. 28, 283–295 (2017).
Rajeev, K. G. et al. Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo. ChemBioChem 16, 903–908 (2015).
Matsuda, S. et al. siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. ACS Chem. Biol. 10, 1181–1187 (2015).
Zimmermann, T. S. et al. Clinical proof of concept for a novel hepatocyte-targeting GalNAc–siRNA conjugate. Mol. Ther. 25, 71–78 (2017).
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).
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).
Foster, D. J. et al. Advanced siRNA designs further improve in vivo performance of GalNAc–siRNA conjugates. Mol. Ther. 26, 708–717 (2018).
Habtemariam, B. A. et al. Single-dose pharmacokinetics and pharmacodynamics of transthyretin targeting N-acetylgalactosamine-small interfering ribonucleic acid conjugate, vutrisiran, in healthy subjects. Clin. Pharmacol. Ther. 109, 372–382 (2021).
Ray, K. K. et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med. 376, 1430–1440 (2017).
Janas, M. M. et al. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity. Nat. Commun. 9, 723 (2018).
Prakash, T. P. et al. Identification of metabolically stable 5′-phosphate analogs that support single-stranded siRNA activity. Nucleic Acids Res. 43, 2993–3011 (2015).
Parmar, R. et al. 5′-(E)-Vinylphosphonate: a stable phosphate mimic can improve the RNAi activity of siRNA-GalNAc conjugates. ChemBioChem 17, 985–989 (2016).
Brown, K. M. et al. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates. Nat. Biotechnol. 40, 1500–1508 (2022).
Janas, M. M. et al. The nonclinical safety profile of GalNAc-conjugated RNAi therapeutics in subacute studies. Toxicol. Pathol. 46, 735–745 (2018).
McDougall, R. et al. The nonclinical disposition and pharmacokinetic/pharmacodynamic properties of N-acetylgalactosamine-conjugated small interfering RNA are highly predictable and build confidence in translation to human. Drug Metab. Dispos. 50, 781–797 (2022).
Larsson, E., Sander, C. & Marks, D. mRNA turnover rate limits siRNA and microRNA efficacy. Mol. Syst. Biol. 6, 433 (2010).
Agarwal, S. et al. Pharmacokinetics and pharmacodynamics of the small interfering ribonucleic acid, givosiran, in patients with acute hepatic porphyria. Clin. Pharmacol. Ther. 108, 63–72 (2020).
Hu, B. et al. Therapeutic siRNA: state of the art. Signal Transduct. Target. Ther. 5, 101 (2020).
Springer, A. D. & Dowdy, S. F. GalNAc–siRNA conjugates: leading the way for delivery of RNAi therapeutics. Nucleic Acid Ther. 28, 109–118 (2018).
Kawasaki, A. M. et al. Uniformly modified 2′-deoxy-2′-fluoro phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets. J. Med. Chem. 36, 831–841 (1993).
Tobin, K. A. Macugen treatment for wet age-related macular degeneration. Insight 31, 11–14 (2006).
McKenzie, R. et al. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N. Engl. J. Med. 333, 1099–1105 (1995).
Richardson, F. C. et al. An evaluation of the toxicities of 2′-fluorouridine and 2′-fluorocytidine-HCl in F344 rats and woodchucks (Marmota monax). Toxicol. Pathol. 27, 607–617 (1999).
Saleh, A. F. et al. 2′-O-(2-methoxyethyl) nucleosides are not phosphorylated or incorporated into the genome of human lymphoblastoid TK6 cells. Toxicol. Sci. 163, 70–78 (2018).
Shen, W., Liang, X. H., Sun, H. & Crooke, S. T. 2′-Fluoro-modified phosphorothioate oligonucleotide can cause rapid degradation of P54nrb and PSF. Nucleic Acids Res. 43, 4569–4578 (2015).
Janas, M. M. et al. Safety evaluation of 2′-deoxy-2′-fluoro nucleotides in GalNAc–siRNA conjugates. Nucleic Acids Res. 47, 3306–3320 (2019).
Ray, K. K. et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol. 11, 109–119 (2023).
Vosberg, H. P. & Eckstein, F. Effect of deoxynucleoside phosphorothioates incorporated in DNA on cleavage by restriction enzymes. J. Biol. Chem. 257, 6595–6599 (1982).
Geary, R. S., Yu, R. Z. & Levin, A. A. Pharmacokinetics of phosphorothioate antisense oligodeoxynucleotides. Curr. Opin. Investig. Drugs 2, 562–573 (2001).
Burgers, P. M. J. & Eckstein, F. Synthesis of dinucleoside monophosphorothioates via addition of sulphur to phosphite triesters. Tetrahedron Lett. 19, 3835–3838 (1978).
Crooke, S. T., Seth, P. P., Vickers, T. A. & Liang, X. H. The interaction of phosphorothioate-containing RNA targeted drugs with proteins is a critical determinant of the therapeutic effects of these Agents. J. Am. Chem. Soc. 142, 14754–14771 (2020).
Frazier, K. S. Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist’s perspective. Toxicol. Pathol. 43, 78–89 (2015).
Janas, M. M. et al. Exposure to siRNA–GalNAc conjugates in systems of the standard test battery for genotoxicity. Nucleic Acid Ther. 26, 363–371 (2016).
Ray, K. K. et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N. Engl. J. Med. 382, 1507–1519 (2020).
Valdmanis, P. N. et al. RNA interference-induced hepatotoxicity results from loss of the first synthesized isoform of microRNA-122 in mice. Nat. Med. 22, 557–562 (2016).
Grimm, D. et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441, 537–541 (2006).
Zlatev, I. et al. Reversal of siRNA-mediated gene silencing in vivo. Nat. Biotechnol. 36, 509–511 (2018).
Jackson, A. L. et al. Expression profiling reveals off-target gene regulation by RNAi. Nat. Biotechnol. 21, 635–637 (2003).
Jackson, A. L. et al. Widespread siRNA ‘off-target’ transcript silencing mediated by seed region sequence complementarity. RNA 12, 1179–1187 (2006).
Birmingham, A. et al. 3′ UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat. Methods 3, 199–204 (2006).
Bramsen, J. B. et al. A screen of chemical modifications identifies position-specific modification by UNA to most potently reduce siRNA off-target effects. Nucleic Acids Res. 38, 5761–5773 (2010).
Vaish, N. et al. Improved specificity of gene silencing by siRNAs containing unlocked nucleobase analogs. Nucleic Acids Res. 39, 1823–1832 (2011).
Schlegel, M. K. et al. From bench to bedside: improving the clinical safety of GalNAc–siRNA conjugates using seed-pairing destabilization. Nucleic Acids Res. 50, 6656–6670 (2022).
Gane, E. et al. Evaluation of RNAi therapeutics VIR-2218 and ALN-HBV for chronic hepatitis B: results from randomized clinical trials. J. Hepatol. 79, 924–932 (2023).
Zhang, M. M., Bahal, R., Rasmussen, T. P., Manautou, J. E. & Zhong, X. B. The growth of siRNA-based therapeutics: updated clinical studies. Biochem. Pharmacol. 189, 114432 (2021).
Grimm, D. Asymmetry in siRNA design. Gene Ther. 16, 827–829 (2009).
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).
Kim, D. H. et al. Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat. Biotechnol. 23, 222–226 (2005).
Zhang, X., Goel, V. & Robbie, G. J. Pharmacokinetics of patisiran, the first approved RNA interference therapy in patients with hereditary transthyretin-mediated amyloidosis. J. Clin. Pharmacol. 60, 573–585 (2019).
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).
Bangalore, S., Breazna, A., DeMicco, D. A., Wun, C.-C. & Messerli, F. H. Visit-to-visit low-density lipoprotein cholesterol variability and risk of cardiovascular outcomes. J. Am. Coll. Cardiol. 65, 1539–1548 (2015).
Fields, T. R. The challenges of approaching and managing gout. Rheum. Dis. Clin. North Am. 45, 145–157 (2019).
Flack, J. M. Epidemiology and unmet needs in hypertension. J. Manag. Care Pharm. 13, 2–8 (2007).
Ceral, J. et al. Difficult-to-control arterial hypertension or uncooperative patients? The assessment of serum antihypertensive drug levels to differentiate non-responsiveness from non-adherence to recommended therapy. Hypertens. Res. 34, 87–90 (2011).
Tomaszewski, M. et al. High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC–MS/MS) urine analysis. Heart 100, 855–861 (2014).
Nelson, M. R. Moving the goalposts for blood pressure—time to act. N. Engl. J. Med. 385, 1328–1329 (2021).
Balakrishnan, K. N. et al. Multiple gene targeting siRNAs for down regulation of Immediate Early-2 (Ie2) and DNA polymerase genes mediated inhibition of novel rat cytomegalovirus (strain All-03). Virol. J. 17, 164 (2020).
Alterman, J. F. et al. A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system. Nat. Biotechnol. 37, 884–894 (2019).
Chernikov, I. V., Vlassov, V. V. & Chernolovskaya, E. L. Current development of siRNA bioconjugates: from research to the clinic. Front. Pharmacol. 10, 444 (2019).
Visscher, P. M. et al. 10 years of GWAS discovery: biology, function, and translation. Am. J. Hum. Genet. 101, 5–22 (2017).
Bellenguez, C. et al. A robust clustering algorithm for identifying problematic samples in genome-wide association studies. Bioinformatics 28, 134–135 (2012).
Jonsson, T. et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488, 96–99 (2012).
Helgadottir, A. et al. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat. Genet. 48, 634–639 (2016).
Plenge, R. M., Scolnick, E. M. & Altshuler, D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013).
King, E. A., Davis, J. W. & Degner, J. F. Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. PLoS Genet. 15, e1008489 (2019).
Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).
Szustakowski, J. D. et al. Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank. Nat. Genet. 53, 942–948 (2021).
Nguyen, P. A., Born, D. A., Deaton, A. M., Nioi, P. & Ward, L. D. Phenotypes associated with genes encoding drug targets are predictive of clinical trial side effects. Nat. Commun. 10, 1579 (2019).
Diogo, D. et al. Phenome-wide association studies across large population cohorts support drug target validation. Nat. Commun. 9, 4285 (2018).
Minikel, E. V. et al. Evaluating drug targets through human loss-of-function genetic variation. Nature 581, 459–464 (2020).
Khan, F. A. et al. CRISPR/Cas9 therapeutics: a cure for cancer and other genetic diseases. Oncotarget 7, 52541–52552 (2016).
Herrera-Carrillo, E., Gao, Z. & Berkhout, B. CRISPR therapy towards an HIV cure. Brief. Funct. Genomics 19, 201–208 (2020).
Gillmore, J. D. et al. CRISPR–Cas9 in vivo gene editing for transthyretin amyloidosis. N. Engl. J. Med. 385, 493–502 (2021).
Wittrup, A. & Lieberman, J. Knocking down disease: a progress report on siRNA therapeutics. Nat. Rev. Genet. 16, 543–552 (2015).
Egeberg, O. Thrombophilia caused by inheritable deficiency of blood antithrombin. Scand. J. Clin. Lab. Invest. 17, 92 (1965).
Pasi, K. J. et al. Targeting of antithrombin in hemophilia A or B with RNAi therapy. N. Engl. J. Med. 377, 819–828 (2017).
Fitzgerald, K. et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N. Engl. J. Med. 376, 41–51 (2017).
Wong, C. H., Siah, K. W. & Lo, A. W. Estimation of clinical trial success rates and related parameters. Biostatistics 20, 273–286 (2019).
Chan, A. et al. Preclinical development of a subcutaneous ALAS1 RNAi therapeutic for treatment of hepatic porphyrias using circulating RNA quantification. Mol. Ther. Nucleic Acids 4, e263 (2015).
Balwani, M. et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N. Engl. J. Med. 382, 2289–2301 (2020).
Garrelfs, S. F. et al. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N. Engl. J. Med. 384, 1216–1226 (2021).
Wright, R. S. et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J. Am. Coll. Cardiol. 77, 1182–1193 (2021).
Adams, D. et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid 30, 1–9 (2023).
Zhu, Y. et al. RNA-based therapeutics: an overview and prospectus. Cell Death Dis. 13, 644 (2022).
Singh, R. N. & Singh, N. N. Mechanism of splicing regulation of spinal muscular atrophy genes. Adv. Neurobiol. 20, 31–61 (2018).
Ackermann, E. J. et al. Suppressing transthyretin production in mice, monkeys and humans using 2nd-generation antisense oligonucleotides. Amyloid 23, 148–157 (2016).
Bartel, D. P. Metazoan microRNAs. Cell 173, 20–51 (2018).
Napoli, C., Lemieux, C. & Jorgensen, R. Introduction of a chimeric chalcone synthase gene into petunia results in reversible co-suppression of homologous genes in trans. Plant Cell. 2, 279–289 (1990).
Soutschek, J. et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432, 173–178 (2004).
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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