Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates
Open accessAbstract
Significant progress has been made in the advancement of RNAi therapeutics by combining a synthetic triantennary N-acetylgalactosamine ligand targeting the asialoglycoprotein receptor with chemically modified small interfering RNA (siRNA) designs, including the recently described Enhanced Stabilization Chemistry. This strategy has demonstrated robust RNAi-mediated gene silencing in liver after subcutaneous administration across species, including human. Here we demonstrate that substantial efficacy improvements can be achieved through further refinement of siRNA chemistry, optimizing the positioning of 2'-deoxy-2'-fluoro and 2'-O-methyl ribosugar modifications across both strands of the double-stranded siRNA duplex to enhance stability without compromising intrinsic RNAi activity. To achieve this, we employed an iterative screening approach across multiple siRNAs to arrive at advanced designs with low 2'-deoxy-2'-fluoro content that yield significantly improved potency and duration in preclinical species, including non-human primate. Liver exposure data indicate that the improvement in potency is predominantly due to increased metabolic stability of the siRNA conjugates.
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The naturally occurring RNAi pathway can be harnessed in extrahepatic organs by building on nearly two decades of liver siRNA design optimization, but novel delivery approaches are needed.
“The naturally occurring RNAi pathway can also be harnessed in extrahepatic organs by building on nearly two decades of efforts on liver siRNA design optimization [9][10][11][12] ; however, novel delivery approaches are needed.”
From Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates (2022) · cites this paper as [9]
The Introduction states that synthetic siRNAs harness the endogenous RNAi pathway and describes targeted delivery to hepatocytes; the Discussion describes further optimization of siRNA designs. The paper does not establish that these designs can be used in extrahepatic organs or state that novel delivery approaches are needed for them. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredFull chemical modification with strategic placement of 2'-fluoro and 2'-O-methyl modifications is required for robust siRNA activity in the CNS.
“Next, we evaluated other siRNA design elements and con rmed that full chemical modi cation with strategic placement of 2'-uoro and 2'-O-methyl modi cations 9 is required for robust siRNA activity in the CNS.”
From Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates (2022) · cites this paper as [9]
The Introduction and Results (page unavailable) describe fully 2′-F/2′-OMe-modified GalNAc-siRNAs and show that modification placement affects activity. But the in vivo experiments measured silencing in liver, not the CNS, and the paper does not establish that full chemical modification is required for robust CNS activity. (LLM, conf=0.88)
Experimental — accuracy not yet measured2'-O-C16 was well tolerated across both sense and antisense strands, with potency similar to the unconjugated siRNA, except for a few positions known to be sensitive to sterically demanding 2'-modifications.
“2'-O-C16 was well tolerated across both strands, with potency similar to the unconjugated siRNA, except for a few positions known to be sensitive to sterically demanding 2'-modi cations 9 .”
From Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates (2022) · cites this paper as [9]
The Introduction and Results describe how sterically demanding 2′ modifications can reduce RNAi activity at particular positions in the sense and antisense strands. But the paper examines 2′-OMe and 2′-F, not 2′-O-C16; it does not establish that 2′-O-C16 was tolerated across both strands or had potency similar to unconjugated siRNA. Page numbers are unavailable in our copy. (LLM, conf=0.79)
Experimental — accuracy not yet measured
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Cites
Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans
Fire, A., Xu, S., Montgomery, M. K., Kostas, S. A., Driver, S. E., & Mello, C. C. (1998) · Nature · doi:10.1038/35888 · Cited by 15,429 · see citing works
Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells
Elbashir, S. M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., & Tuschl, T. (2001) · Nature · doi:10.1038/35078107 · Cited by 9,456 · see citing works
Hannon, G. J. (2002) · Nature · doi:10.1038/418244a · Cited by 3,583 · see citing works
Nair, J. K., Willoughby, J. L. S., Chan, A., Charisse, K., Alam, M. R., Wang, Q., Hoekstra, M., Kandasamy, P., Kel’in, A. V., Milstein, S., et al. (2014) · Journal of the American Chemical Society · doi:10.1021/ja505986a · Cited by 1,141 · see citing works
Self-citationSafety and efficacy of RNAi therapy for transthyretin amyloidosis
Coelho, T., Adams, D., Silva, A., Lozeron, P., Hawkins, P. N., Mant, T., Perez, J., Chiesa, J., Warrington, S., Tranter, E., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1208760 · Cited by 971 · see citing works
Self-citationsiRNA function in RNAi: A chemical modification analysis
Chiu, Y., & Rana, T. M. (2003) · RNA · doi:10.1261/rna.5103703 · Cited by 863 · see citing works
Knocking down disease: a progress report on siRNA therapeutics
Wittrup, A., & Lieberman, J. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3978 · Cited by 810 · see citing works
A highly durable RNAi therapeutic inhibitor of PCSK9
Fitzgerald, K., White, S., Borodovsky, A., Bettencourt, B. R., Strahs, A., Clausen, V., Wijngaard, P., Horton, J. D., Taubel, J., Brooks, A., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1609243 · Cited by 768 · see citing works
Frank-Kamenetsky, M. D., Grefhorst, A., Anderson, N. N., Racie, T., Bramlage, B., Akinc, A., Butler, D., Charissé, K., Dorkin, J. R., Fan, Y., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805434105 · Cited by 635 · see citing works
Self-citationFitzgerald, K. J., Frank-Kamenetsky, M. D., Shulga‐Morskaya, S., Liebow, A., Bettencourt, B. R., Sutherland, J. E., Hutabarat, R. M., Clausen, V. A., Karsten, V., Cehelsky, J. E., et al. (2013) · The Lancet · doi:10.1016/s0140-6736(13)61914-5 · Cited by 574 · see citing works
The Ashwell receptor mitigates the lethal coagulopathy of sepsis
Grewal, P. K., Uchiyama, S., Ditto, D., Varki, N., Le, D. T., Nizet, V., & Marth, J. D. (2008) · Nature Medicine · doi:10.1038/nm1760 · Cited by 374 · see citing works
Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy
Pasi, J., Rangarajan, S., Georgiev, P., Mant, T., Creagh, M. D., Lissitchkov, T. J., Bevan, D. H., Austin, S. K., Hay, C. R. M., Hegemann, I., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1616569 · Cited by 369 · see citing works
Cummins, L. L., Owens, S. R., Risen, L. M., Lesnik, E. A., Freier, S., McGee, D. P. C., Guinosso, C. J., & Cook, P. D. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.11.2019 · Cited by 364 · see citing works
RNA Interference (RNAi)-Based Therapeutics: Delivering on the Promise?
Bobbin, M. L., & Rossi, J. J. (2016) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103633 · Cited by 352 · see citing works
Bramsen, J. B., Laursen, M. B., Nielsen, A. F., Hansen, T. B., Bus, C., Langkjær, N., Babu, B. R., Højland, T., Abramov, M., Van Aerschot, A., et al. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp106 · Cited by 332 · see citing works
Sehgal, A., Barros, S. A., Ivanciu, L., Cooley, B. C., Qin, J., Racie, T., Hettinger, J. L., Carioto, M., Jiang, Y., Brodsky, J., et al. (2015) · Nature Medicine · doi:10.1038/nm.3847 · Cited by 307 · see citing works
Self-citationPositional Effect of Chemical Modifications on Short Interference RNA Activity in Mammalian Cells
Prakash, T. P., Allerson, C. R., Dande, P., Vickers, T. A., Sioufi, N. B., Jarres, R., Baker, B. F., Swayze, E. E., Griffey, R. H., & Bhat, B. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050044o · Cited by 285 · see citing works
Nair, J. K., Attarwala, H., Sehgal, A., Wang, Q., Aluri, K., Zhang, X., Gao, M., Liu, J., Indrakanti, R., Schofield, S., et al. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx818 · Cited by 278 · see citing works
Self-citationMatsuda, S., Keiser, K., Nair, J. K., Charissé, K., Manoharan, R. M., Kretschmer, P., Peng, C. G., Kel’in, A. V., Pachamuthu, K., Willoughby, J. L. S., et al. (2015) · ACS Chemical Biology · doi:10.1021/cb501028c · Cited by 222 · see citing works
Self-citationUnique Gene‐Silencing and Structural Properties of 2′‐Fluoro‐Modified siRNAs
Manoharan, M., Akinc, A., Pandey, R. K., Qin, J., Hadwiger, P., John, M., Mills, K., Charissé, K., Maier, M. A., Nechev, L. V., et al. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201006519 · Cited by 194 · see citing works
Self-citationTrivalent, Gal/GalNAc-containing ligands designed for the asialoglycoprotein receptor
Khorev, O., Stokmaier, D., Schwardt, O., Cutting, B., & Ernst, B. (2008) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2008.03.017 · Cited by 147 · see citing works
Chan, A., Liebow, A., Yasuda, M., Gan, L., Racie, T., Maier, M., Kuchimanchi, S., Foster, D., Milstein, S., Charisse, K., et al. (2015) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2015.36 · Cited by 128 · see citing works
Self-citation2′-Fluoro-modified phosphorothioate oligonucleotide can cause rapid degradation of P54nrb and PSF
Shen, W., Liang, X., Sun, H., & Crooke, S. T. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv298 · Cited by 109 · see citing works
Rensen, P. C. N., van Leeuwen, S. H., Sliedregt, L. A. J. M., van Berkel, T. J. C., & Biessen, E. A. L. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm049481d · Cited by 87 · see citing works
Takahashi, M. M., Minakawa, N., & Matsuda, A. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn1088 · Cited by 73 · see citing works
[87] A membrane receptor protein for asialoglycoproteins
Pricer, W. E., Hudgin, R. L., Ashwell, G., Stockert, R. J., & Morell, A. G. (1974) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(74)34090-6 · Cited by 58 · see citing works
Solid-phase synthesis of siRNA oligonucleotides.
Beaucage, S. L. (2008) · PubMed · Cited by 55 · see citing works
Current Strategies for the Synthesis of RNA
Müller, S., Wolf, J., & Ivanov, S. (2004) · Current Organic Synthesis · doi:10.2174/1570179043366675 · Cited by 50 · see citing works
Valentijn, A. R. P. M., van der Marel, G. A., Sliedregt, L. A. J. M., van Berkel, T. J. C., Biessen, E. A. L., & BOOM, J. H. V. (1997) · Tetrahedron · doi:10.1016/s0040-4020(96)01018-6 · Cited by 48 · see citing works
Impact of Oligonucleotide Structure, Chemistry, and Delivery Method on In Vitro Cytotoxicity
Janas, M. M., Jiang, Y., Schlegel, M. K., Waldron, S., Kuchimanchi, S., & Barros, S. A. (2016) · Nucleic Acid Therapeutics · doi:10.1089/nat.2016.0639 · Cited by 45 · see citing works
Self-citationExposure to siRNA-GalNAc Conjugates in Systems of the Standard Test Battery for Genotoxicity
Janas, M. M., Jiang, Y., Duncan, R. G., Hayes, A., Liu, J., Kasperkovitz, P. V., Placke, M. E., & Barros, S. A. (2016) · Nucleic Acid Therapeutics · doi:10.1089/nat.2016.0622 · Cited by 27 · see citing works
Flagged first, then by citations
1 of the 32 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Therapeutic siRNA: state of the art
Hu, B., Zhong, L., Weng, Y., Peng, L., Huang, Y., Zhao, Y., & Liang, X.-J. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0207-x · Cited by 1,586 · see citing works
The current landscape of nucleic acid therapeutics
Kulkarni, J. A., Witzigmann, D., Thomson, S. B., Chen, S., Leavitt, B. R., Cullis, P. R., & van der Meel, R. (2021) · Nature Nanotechnology · doi:10.1038/s41565-021-00898-0 · Cited by 1,371 · see citing works
Drug delivery systems for RNA therapeutics
Paunovska, K., Loughrey, D., & Dahlman, J. E. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-021-00439-4 · Cited by 1,349 · see citing works
Chemistry, structure and function of approved oligonucleotide therapeutics
Egli, M., & Manoharan, M. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad067 · Cited by 864 · see citing works
Self-citationAntisense technology: an overview and prospectus
Crooke, S. T., Baker, B. F., Crooke, R. M., & Liang, X.-H. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00162-z · Cited by 775 · see citing works
The growth of siRNA-based therapeutics: updated clinical studies
Zhang, M. M., Bahal, R., Rasmussen, T. P., Manautou, J. E., & Zhong, X.-B. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114432 · Cited by 497 · see citing works
Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug
Debacker, A. J., Voutila, J., Catley, M. C., Blakey, D. C., & Habib, N. A. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.06.015 · Cited by 403 · see citing works
Therapeutic siRNA: State-of-the-Art and Future Perspectives
Friedrich, M., & Aigner, A. M. (2022) · BioDrugs · doi:10.1007/s40259-022-00549-3 · Cited by 413 · see citing works
Lipid nanoparticle technology for therapeutic gene regulation in the liver
Witzigmann, D., Kulkarni, J. A., Leung, J., Chen, S., Cullis, P. R., & van der Meel, R. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.06.026 · Cited by 376 · see citing works
RNAi-based drug design: considerations and future directions
Tang, Q., & Khvorova, A. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-00912-9 · Cited by 309 · see citing works
RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies
Traber, G. M., & Yu, A. (2022) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.122.001234 · Cited by 301 · see citing works
siRNA therapeutics: a clinical reality
Saw, P. E., & Song, E. (2019) · Science China Life Sciences · doi:10.1007/s11427-018-9438-y · Cited by 292 · see citing works
Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates
Brown, C. R., Gupta, S., Qin, J., Racie, T., He, G., Lentini, S., Malone, R., Yu, M., Matsuda, S., Shulga-Morskaya, S., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa670 · Cited by 285 · see citing works
Self-citationSelection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity
Janas, M. M., Schlegel, M. K., Harbison, C. E., Yilmaz, V. O., Jiang, Y., Parmar, R., Zlatev, I., Castoreno, A., Xu, H., Shulga-Morskaya, S., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-02989-4 · Cited by 279 · see citing works
Self-citationNoncoding RNAs in cancer therapy resistance and targeted drug development
Wang, W., Han, C., Sun, Y., Chen, T.-Q., & Chen, Y. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0748-z · Cited by 266 · see citing works
Multispecific drugs herald a new era of biopharmaceutical innovation
Deshaies, R. J. (2020) · Nature · doi:10.1038/s41586-020-2168-1 · Cited by 262 · see citing works
Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates
Brown, K. M., Nair, J. K., Janas, M. M., Anglero-Rodriguez, Y. I., Dang, L. T. H., Peng, H., Theile, C. S., Castellanos-Rizaldos, E., Brown, C., Foster, D., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01334-x · Cited by 258 · see citing works
Self-citationCurrent Development of siRNA Bioconjugates: From Research to the Clinic
Chernikov, I. V., Vlassov, V. V., & Chernolovskaya, E. L. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00444 · Cited by 216 · see citing works
RNA interference in the era of nucleic acid therapeutics
Jadhav, V., Vaishnaw, A. K., Fitzgerald, K. J., & Maier, M. A. (2024) · Nature Biotechnology · doi:10.1038/s41587-023-02105-y · Cited by 218 · see citing works
Self-citationDiverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo
Biscans, A., Coles, A. H., Haraszti, R. Á., Echeverria, D., Hassler, M. R., Osborn, M. F., & Khvorova, A. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1239 · Cited by 206 · see citing works
Nucleic acid drugs: recent progress and future perspectives
Sun, X., Setrerrahmane, S., Li, C., Hu, J., & Xu, H. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02035-4 · Cited by 202 · see citing works
Habtemariam, B. A., Karsten, V., Attarwala, H. Z., Goel, V., Melch, M., Clausen, V. A., Garg, P. P., Vaishnaw, A. K., Sweetser, M. T., Robbie, G. J., et al. (2020) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1974 · Cited by 181 · see citing works
RNA therapy: Are we using the right molecules?
Yu, A., Jian, C., Yu, A. H., & Tu, M. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.11.011 · Cited by 162 · see citing works
Clinical advances of siRNA therapeutics
Hu, B., Weng, Y., Xia, X., Liang, X., & Huang, Y. (2019) · The Journal of Gene Medicine · doi:10.1002/jgm.3097 · Cited by 157 · see citing works
Targeted tissue delivery of RNA therapeutics using antibody–oligonucleotide conjugates (AOCs)
Malecová, B., Burke, R. S., Cochran, M., Hood, M. D., Johns, R. E., Kovach, P., Doppalapudi, V. R., Erdogan, G., Arias, J. D., Darimont, B. D., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad415 · Cited by 160 · see citing works
Barbier‐Torres, L., Fortner, K. A., Iruzubieta, P., Delgado, T. C., Giddings, E. L., Chen, Y., Champagne, D., Fernández‐Ramos, D., Mestre, D., Gómez‐Santos, B., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16991-2 · Cited by 142 · see citing works
Michler, T., Kosinska, A. D., Festag, J., Bunse, T., Su, J., Ringelhan, M., Imhof, H., Grimm, D., Steiger, K., Mogler, C., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.01.032 · Cited by 130 · see citing works
Self-citationMcDougall, R., Ramsden, D., Agarwal, S., Agarwal, S., Aluri, K. C., Arciprete, M., Brown, C. R., Castellanos-Rizaldos, E., Charissé, K., Chong, S., et al. (2021) · Drug Metabolism and Disposition · doi:10.1124/dmd.121.000428 · Cited by 115 · see citing works
Self-citationJudge, D. P., Kristen, A. V., Grogan, M. A., Maurer, M. S., Falk, R. H., Hanna, M. A., Gillmore, J. D., Garg, P. P., Vaishnaw, A. K., Harrop, J., et al. (2020) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-019-06919-4 · Cited by 110 · see citing works
Antisense drug discovery and development technology considered in a pharmacological context
Crooke, S. T., Liang, X., Crooke, R. M., Baker, B. F., & Geary, R. S. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114196 · Cited by 104 · see citing works
Schlegel, M. K., Janas, M. M., Jiang, Y., Barry, J. D., Davis, W. P., Agarwal, S., Berman, D., Brown, C. R., Castoreno, A. B., LeBlanc, S., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac539 · Cited by 101 · see citing works
Self-citationPolymeric Carriers for Nucleic Acid Delivery: Current Designs and Future Directions
Peng, L., & Wagner, E. (2019) · Biomacromolecules · doi:10.1021/acs.biomac.9b00999 · Cited by 100 · see citing works
Current Aspects of siRNA Bioconjugate for In Vitro and In Vivo Delivery
Tai, W. (2019) · Molecules · doi:10.3390/molecules24122211 · Cited by 97 · see citing works
Reversal of siRNA-mediated gene silencing in vivo
Zlatev, I., Castoreno, A. B., Brown, C. R., Qin, J., Waldron, S., Schlegel, M. K., Degaonkar, R., Shulga‐Morskaya, S., Xu, H., Gupta, S., et al. (2018) · Nature Biotechnology · doi:10.1038/nbt.4136 · Cited by 96 · see citing works
Self-citationJahns, H., Taneja, N., Willoughby, J. L. S., Akabane‐Nakata, M., Brown, C. R., Nguyen, T. M., Bisbe, A., Matsuda, S., Hettinger, M., Manoharan, R. M., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab544 · Cited by 91 · see citing works
Self-citationFrameworks for transformational breakthroughs in RNA-based medicines
Androsavich, J. R. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-00943-2 · Cited by 93 · see citing works
Advances with RNAi-Based Therapy for Hepatitis B Virus Infection
van den Berg, F. T., Limani, S. W., Mnyandu, N., Maepa, M. B., Ely, A., & Arbuthnot, P. B. (2020) · Viruses · doi:10.3390/v12080851 · Cited by 87 · see citing works
siRNA Functionalized Lipid Nanoparticles (LNPs) in Management of Diseases
Kalita, T., Dezfouli, S. A., Pandey, L. M., & Uludağ, H. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14112520 · Cited by 87 · see citing works
Testing thousands of nanoparticles in vivo using DNA barcodes
Lokugamage, M. P., Sago, C. D., & Dahlman, J. E. (2018) · Current Opinion in Biomedical Engineering · doi:10.1016/j.cobme.2018.08.001 · Cited by 81 · see citing works
Gait, M. J., Arzumanov, A. A., McClorey, G., Godfrey, C., Betts, C., Hammond, S. M., & Wood, M. J. A. (2018) · Nucleic Acid Therapeutics · doi:10.1089/nat.2018.0747 · Cited by 83 · see citing works
Optimizing synthetic nucleic acid and protein nanocarriers: The chemical evolution approach
Freitag, F., & Wagner, E. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.03.005 · Cited by 82 · see citing works
The Nonclinical Safety Profile of GalNAc-conjugated RNAi Therapeutics in Subacute Studies
Janas, M. M., Harbison, C. E., Perry, V. K., Carito, B. A., Sutherland, J. E., Vaishnaw, A. K., Keirstead, N. D., & Warner, G. L. (2018) · Toxicologic Pathology · doi:10.1177/0192623318792537 · Cited by 82 · see citing works
Ex-vivo Kidney Machine Perfusion: Therapeutic Potential
Žulpaitė, R., Miknevicius, P., Leber, B., Strupas, K., Stiegler, P., & Schemmer, P. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.808719 · Cited by 81 · see citing works
Uehara, K., Harumoto, T., Makino, A., Koda, Y., Iwano, J., Suzuki, Y., Tanigawa, M., Iwai, H., Asano, K., Kurihara, K., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac308 · Cited by 79 · see citing works
Safety evaluation of 2′-deoxy-2′-fluoro nucleotides in GalNAc-siRNA conjugates
Janas, M. M., Zlatev, I., Liu, J., Jiang, Y., Barros, S. A., Sutherland, J. E., Davis, W. P., Liu, J., Brown, C. R., Liu, X., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz140 · Cited by 82 · see citing works
Self-citationBadri, P. S., Jiang, X., Borodovsky, A., Najafian, N., Kim, J. B., Clausen, V. A., Goel, V., Habtemariam, B. A., & Robbie, G. J. (2020) · Clinical Pharmacokinetics · doi:10.1007/s40262-020-00940-9 · Cited by 79 · see citing works
Pharmacokinetics and Pharmacodynamics of GalNAc‐Conjugated siRNAs
An, G. (2023) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.2337 · Cited by 85 · see citing works
Gao, Y., Tong, M., Wong, T. L., Ng, K. Y., Xie, Y., Wang, Z., Yu, H., Loh, J.-J., Li, M., & Ma, S. (2023) · ACS Nano · doi:10.1021/acsnano.3c01199 · Cited by 77 · see citing works
Biscans, A., Caiazzi, J., McHugh, N., Hariharan, V. N., Muhuri, M., & Khvorova, A. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.12.023 · Cited by 75 · see citing works
Jin, Y., Zhang, B., Li, J., Guo, Z., Zhang, C., Chen, X., Ma, L., Wang, Z., Yang, H., Li, Y., et al. (2025) · Science Advances · doi:10.1126/sciadv.adr9266 · Cited by 74 · see citing works
Biscans, A., Caiazzi, J., Davis, S. M., McHugh, N., Sousa, J., & Khvorova, A. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa595 · Cited by 68 · see citing works
Shmushkovich, T., Monopoli, K. R., Homsy, D., Leyfer, D., Betancur-Boissel, M., Khvorova, A., & Wolfson, A. D. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky745 · Cited by 72 · see citing works
Yuzefovych, Y., Valdivia, E., Rong, S., Hack, F., Rother, T., Schmitz, J., Bräsen, J. H., Wedekind, D., Moers, C., Wenzel, N., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00265 · Cited by 70 · see citing works
Using Large Datasets to Understand Nanotechnology
Paunovska, K., Loughrey, D., Sago, C. D., Langer, R., & Dahlman, J. E. (2019) · Advanced Materials · doi:10.1002/adma.201902798 · Cited by 67 · see citing works
Overcoming the challenges of tissue delivery for oligonucleotide therapeutics
Gökirmak, T., Nikan, M., Wiechmann, S., Prakash, T. P., Tanowitz, M., & Seth, P. P. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.04.010 · Cited by 69 · see citing works
Mammalian sugar‐binding receptors: known functions and unexplored roles
Taylor, M. E., & Drickamer, K. (2019) · FEBS Journal · doi:10.1111/febs.14759 · Cited by 67 · see citing works
Ambike, S. S., Cheng, C., Feuerherd, M., Velkov, S., Baldassi, D., Afridi, S. Q., Porras-Gonzalez, D., Wei, X. C., Hagen, P., Kneidinger, N., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab1248 · Cited by 66 · see citing works
de Paula Brandão, P. R., Titze-de-Almeida, S. S., & Titze-de-Almeida, R. (2020) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-019-00438-6 · Cited by 72 · see citing works
A holistic analysis of the intrinsic and delivery-mediated toxicity of siRNA therapeutics
Ranjbar, S., Zhong, X., Manautou, J. E., & Lü, X. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.115052 · Cited by 69 · see citing works
Factor XII/XIIa inhibitors: Their discovery, development, and potential indications
Davoine, C., Bouckaert, C., Fillet, M., & Pochet, L. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112753 · Cited by 63 · see citing works
Ongoing Clinical Trials of Nonviral siRNA Therapeutics
Narasipura, E. A., VanKeulen‐Miller, R., Ma, Y., & Fenton, O. S. (2023) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.3c00205 · Cited by 63 · see citing works
Breaking the mold with RNA—a “RNAissance” of life science
Jones, C. H., Androsavich, J. R., So, N., Jenkins, M. P., MacCormack, D., Prigodich, A. E., Welch, V., True, J. M., & Dolsten, M. (2024) · npj Genomic Medicine · doi:10.1038/s41525-023-00387-4 · Cited by 65 · see citing works
Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1
Davis, S. M., Hariharan, V. N., Lo, A. S., Turanov, A. A., Echeverria, D., Sousa, J., McHugh, N., Biscans, A., Alterman, J. F., Karumanchi, S. A., et al. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.06.009 · Cited by 59 · see citing works
Antithrombin-lowering in hemophilia: a closer look at fitusiran
Young, G. A., Lenting, P. J., Croteau, S. E., Nolan, B., & Srivastava, A. (2023) · Research and Practice in Thrombosis and Haemostasis · doi:10.1016/j.rpth.2023.100179 · Cited by 59 · see citing works
Development, opportunities, and challenges of siRNA nucleic acid drugs
Xiao, B., Wang, S., Pan, Y., Zhi, W., Gu, C., Guo, T., Zhai, J., Li, C., Chen, Y. Q., & Wang, R. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102437 · Cited by 64 · see citing works
Enhancing siRNA efficacy in vivo with extended nucleic acid backbones
Yamada, K., Hariharan, V. N., Caiazzi, J., Miller, R., Ferguson, C. M., Sapp, E., Fakih, H. H., Tang, Q., Yamada, N., Furgal, R. C., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02336-7 · Cited by 59 · see citing works
Generation and validation of structurally defined antibody–siRNA conjugates
Nanna, A. R., Kel’in, A. V., Theile, C. S., Pierson, J. M., Voo, Z. X., Garg, A., Nair, J. K., Maier, M. A., Fitzgerald, K. J., & Rader, C. M. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa286 · Cited by 55 · see citing works
Self-citationInnovative developments and emerging technologies in RNA therapeutics
Halloy, F., Biscans, A., Bujold, K. E., Debacker, A. J., Hill, A. C., Lacroix, A., Luige, O., Strömberg, R., Sundström, L., Vogel, J., et al. (2022) · RNA Biology · doi:10.1080/15476286.2022.2027150 · Cited by 54 · see citing works
Sutton, J. M., Kim, J., Zahar, N. M. E., & Bartlett, M. G. (2020) · Mass Spectrometry Reviews · doi:10.1002/mas.21641 · Cited by 54 · see citing works
Cochran, M., Arias, D., Burke, R. S., Chu, D., Erdogan, G., Hood, M., Kovach, P., Kwon, H. W., Chen, Y., Moon, M., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00802 · Cited by 53 · see citing works
Zhong, Y., Chi, F., Wu, H., Liu, Y., Xie, Z., Huang, W., Shi, W., & Qian, H. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114142 · Cited by 51 · see citing works
Dang, B.-T. N., Duwa, R., Lee, S., Kwon, T. K., Chang, J., Jeong, J., & Yook, S. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.06.062 · Cited by 52 · see citing works
Gangopadhyay, S., Nikam, R. R., & Gore, K. R. (2021) · Nucleic Acid Therapeutics · doi:10.1089/nat.2020.0882 · Cited by 53 · see citing works
Modulating intracellular pathways to improve non-viral delivery of RNA therapeutics
de Vyver, T. V., Smedt, S. C. D., & Raemdonck, K. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114041 · Cited by 51 · see citing works
Anand, P., Zhang, Y., Patil, S., & Kaur, K. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02528 · Cited by 51 · see citing works
Judge, D. P., Kristen, A. V., Grogan, M. A., Maurer, M. S., Falk, R. H., Hanna, M. A., Gillmore, J. D., Garg, P. P., Vaishnaw, A. K., Harrop, J., et al. (2020) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-020-07023-8 · Cited by 51 · see citing works
Humphreys, S. C., Davis, J. A., Iqbal, S., Kamel, A. M., Kulmatycki, K. M., Lao, Y., Liu, X., Rodgers, J., Snoeys, J., Vigil, A., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac456 · Cited by 50 · see citing works
Engineered ionizable lipid siRNA conjugates enhance endosomal escape but induce toxicity in vivo
Biscans, A., Ly, S., McHugh, N., Cooper, D., & Khvorova, A. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.07.041 · Cited by 50 · see citing works
Conroy, F., Miller, R., Alterman, J. F., Hassler, M. R., Echeverria, D., Godinho, B. M. D. C., Knox, E. G., Sapp, E., Sousa, J., Yamada, K., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33061-x · Cited by 50 · see citing works
The therapeutic prospects of N-acetylgalactosamine-siRNA conjugates
Zhang, L., Liang, Y., Liang, G., Tian, Z., Zhang, Y., Liu, Z., & Ji, X. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1090237 · Cited by 50 · see citing works
Harp, J. M., Guenther, D. C., Bisbe, A., Perkins, L. A., Matsuda, S., Bommineni, G. R., Zlatev, I., Foster, D. J., Taneja, N., Charissé, K., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky703 · Cited by 49 · see citing works
Self-citationCentyrin ligands for extrahepatic delivery of siRNA
Klein, D., Goldberg, S. D., Theile, C. S., Dambra, R., Haskell, K., Kuhar, E., Lin, T., Parmar, R. G., Manoharan, M., Richter, M. C., et al. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.02.015 · Cited by 48 · see citing works
Self-citationInnate immune regulations and various siRNA modalities
Kaushal, A. (2023) · Drug Delivery and Translational Research · doi:10.1007/s13346-023-01361-4 · Cited by 49 · see citing works
Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection
Hariharan, V. N., Shin, M., Chang, C., O’Reilly, D., Biscans, A., Yamada, K., Guo, Z., Somasundaran, M., Tang, Q., Monopoli, K. R., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2219523120 · Cited by 48 · see citing works
The Growing Class of Novel RNAi Therapeutics
Traber, G. M., & Yu, A. (2024) · Molecular Pharmacology · doi:10.1124/molpharm.124.000895 · Cited by 46 · see citing works
Inhibition of SARS-CoV-2 replication in the lung with siRNA/VIPER polyplexes
Baldassi, D., Ambike, S. S., Feuerherd, M., Cheng, C., Peeler, D. J., Feldmann, D. P., Porras-Gonzalez, D., Wei, X. C., Keller, L.-A., Kneidinger, N., et al. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.03.051 · Cited by 47 · see citing works
Egli, M., Schlegel, M. K., & Manoharan, M. (2023) · RNA · doi:10.1261/rna.079526.122 · Cited by 45 · see citing works
Self-citationStructural Modifications of siRNA Improve Its Performance In Vivo
Chernikov, I. V., Ponomareva, U. A., & Chernolovskaya, E. L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24020956 · Cited by 44 · see citing works
Liu, W., Iwamoto, N., Marappan, S., Luu, K., Tripathi, S., Purcell-Estabrook, E., Shelke, J. D., Shah, H., Lamattina, A., Pan, Q., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad268 · Cited by 44 · see citing works
Sharma, V., Osborn, M. F., Hassler, M. R., Echeverria, D., Ly, S., Ulashchik, E. A., Martynenko-Makaev, Y. V., Shmanai, V. V., Zatsepin, T. S., Khvorova, A., et al. (2018) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.8b00365 · Cited by 42 · see citing works
Zhao, B., Zhou, B., Shi, K. Y., Zhang, R., Dong, C., Xie, D., Tang, L., Tian, Y., Qian, Z., & Li, Y. (2021) · Cancer Science · doi:10.1111/cas.14903 · Cited by 43 · see citing works
Li, J., Liu, J., Zhang, X., Clausen, V. A., Tran, C., Arciprete, M., Wang, Q., Rocca, C., Guan, L.-H., Zhang, G., et al. (2021) · Drug Metabolism and Disposition · doi:10.1124/dmd.121.000381 · Cited by 43 · see citing works
Motamedi, H., Ari, M. M., Alvandi, A., & Abiri, R. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1393646 · Cited by 42 · see citing works
Peters-Clarke, T. M., Quan, Q., Brademan, D. R., Hebert, A. S., Westphall, M., & Coon, J. (2020) · Analytical Chemistry · doi:10.1021/acs.analchem.9b05388 · Cited by 34 · see citing works
Less Is More: Novel Hepatocyte-Targeted siRNA Conjugates for Treatment of Liver-Related Disorders
Weingärtner, A., Bethge, L., Weiss, L., Sternberger, M., & Lindholm, M. (2020) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2020.05.026 · Cited by 41 · see citing works
Ly, S., Echeverria, D., Sousa, J., & Khvorova, A. (2020) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2020.07.029 · Cited by 38 · see citing works
Liu, J., Qin, J., Borodovsky, A., Racie, T., Castoreno, A. B., Schlegel, M. K., Maier, M. A., Zimmerman, T., Fitzgerald, K. J., Butler, J. T., et al. (2018) · RNA · doi:10.1261/rna.068916.118 · Cited by 40 · see citing works
Self-citationLucas, A. T., Moody, A., Schorzman, A. N., & Zamboni, W. C. (2021) · Antibodies · doi:10.3390/antib10030030 · Cited by 40 · see citing works
Xu, J., Gu, M., Hooi, L., Toh, T. B., Thng, D. K. H., Lim, J. J., & Chow, E. K. (2021) · Nanoscale · doi:10.1039/d1nr03502a · Cited by 40 · see citing works
Precision medicine and nucleotide-based therapeutics to treat steatotic liver disease
Caddeo, A. M., & Romeo, S. (2024) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.0438 · Cited by 41 · see citing works
- Authors
- Foster, D. J., Brown, C. R., Shaikh, S., Trapp, C., Schlegel, M. K., Qian, K., Sehgal, A., Rajeev, K. G., Jadhav, V., Manoharan, M., Kuchimanchi, S., Maier, M. A., & Milstein, S.
- Affiliations
- Alnylam Pharmaceuticals (United States) (US)
- Corresponding author
- Milstein, Stuart
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 26
- Issue
- 3
- Pages
- 708-717
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC5910670
- OpenAlex
- W2781906140
- Cited by
- 325
- References
- 32
- Citations by year
- 2026: 41 · 2025: 46 · 2024: 49 · 2023: 34 · 2022: 34 · 2021: 37 · 2020: 43 · 2019: 24 · 2018: 17
- FWCI
- 10.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- siRNA design, RNAi therapeutics, asialoglycoprotein receptor, siRNA stability, non-human primates, subcutaneous administration
- MeSH terms
- Acetylgalactosamine, Animals, Gene Expression Regulation, Liver, Male, Mice, Transgenic, RNA, Messenger, Gene Silencing, Hepatocytes, RNA Interference, RNA, Small Interfering, Mice, Argonaute Proteins
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