Multivalent N -Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing
Abstract
Conjugation of small interfering RNA (siRNA) to an asialoglycoprotein receptor ligand derived from N-acetylgalactosamine (GalNAc) facilitates targeted delivery of the siRNA to hepatocytes in vitro and in vivo. The ligands derived from GalNAc are compatible with solid-phase oligonucleotide synthesis and deprotection conditions, with synthesis yields comparable to those of standard oligonucleotides. Subcutaneous (SC) administration of siRNA-GalNAc conjugates resulted in robust RNAi-mediated gene silencing in liver. Refinement of the siRNA chemistry achieved a 5-fold improvement in efficacy over the parent design in vivo with a median effective dose (ED50) of 1 mg/kg following a single dose. This enabled the SC administration of siRNA-GalNAc conjugates at therapeutically relevant doses and, importantly, at dose volumes of ≤1 mL. Chronic weekly dosing resulted in sustained dose-dependent gene silencing for over 9 months with no adverse effects in rodents. The optimally chemically modified siRNA-GalNAc conjugates are hepatotropic and long-acting and have the potential to treat a wide range of diseases involving liver-expressed genes.
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GalNAc-siRNA conjugates achieve systemic stability against nucleases, improving pharmacokinetics.
“Results showed that by conjugating the engineered ASGPR ligand to the chemically modified siRNA molecule, GalNAc-siRNA conjugates could achieve systemic stability against nucleases, which would in turn improve pharmacokinetics.”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [77]
Single or multiple low-volume subcutaneous injections of GalNAc-siRNA conjugates resulted in effective suppression of the target gene in the liver.
“Most importantly, single or multiple low-volume subcutaneous injections of these conjugates resulted in effective suppression of the target gene in the liver.[51, 77, 78]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [77]
ASGPR is highly expressed on hepatocytes and GalNAc facilitates uptake of its payload into hepatocytes through ASGPR via clathrin-mediated endocytosis.
“The ASGPR is highly expressed on hepatocytes and GalNAc facilitates the uptake of its payload into hepatocytes through ASGPR via clathrin-mediated endocytosis.[77]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [77]
Cites
A Receptor-Mediated Pathway for Cholesterol Homeostasis
Brown, M. S., & Goldstein, J. L. (1986) · Science · doi:10.1126/science.3513311 · Cited by 5,703 · see citing works
Brown, M. S., & Goldstein, J. L. (1997) · Cell · doi:10.1016/s0092-8674(00)80213-5 · Cited by 3,834 · see citing works
Biological, clinical and population relevance of 95 loci for blood lipids
Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., et al. (2010) · Nature · doi:10.1038/nature09270 · Cited by 3,487 · see citing works
Mutations in PCSK9 cause autosomal dominant hypercholesterolemia
Abifadel, M., Varret, M., Rabès, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., et al. (2003) · Nature Genetics · doi:10.1038/ng1161 · Cited by 2,985 · see citing works
Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles
Davis, M. E., Zuckerman, J. E., Choi, C. H. J., Seligson, D. B., Tolcher, A. W., Alabi, C. A., Yen, Y., Heidel, J. D., & Ribas, A. (2010) · Nature · doi:10.1038/nature08956 · Cited by 2,508 · see citing works
Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., & Hobbs, H. H. (2005) · Nature Genetics · doi:10.1038/ng1509 · Cited by 1,381 · see citing works
RNAi therapeutics: a potential new class of pharmaceutical drugs
Bumcrot, D. A., Manoharan, M., Koteliansky, V., & Sah, D. W. Y. (2006) · Nature Chemical Biology · doi:10.1038/nchembio839 · Cited by 1,086 · see citing works
Self-citationMechanisms and optimization of in vivo delivery of lipophilic siRNAs
Wolfrum, C., Shi, S., Jayaprakash, K. N., Jayaraman, M., Wang, G., Pandey, R. K., Rajeev, K. G., Nakayama, T., Charrise, K., Ndungo, E. M., et al. (2007) · Nature Biotechnology · doi:10.1038/nbt1339 · Cited by 974 · 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-citationA new solid-state reagent to iodinate proteins
Markwell, M. A. K. (1982) · Analytical Biochemistry · doi:10.1016/0003-2697(82)90025-2 · Cited by 875 · see citing works
LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor
Zelcer, N., Hong, C., Boyadjian, R., & Tontonoz, P. (2009) · Science · doi:10.1126/science.1168974 · Cited by 848 · see citing works
Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes
Rozema, D. B., Lewis, D. L., Wakefield, D. H., Wong, S. C., Klein, J. J., Roesch, P. L., Bertin, S. L., Reppen, T. W., Chu, Q., Blokhin, A. V., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703778104 · Cited by 658 · see citing works
Maier, M. A., Jayaraman, M., Matsuda, S., Liu, J., Barros, S., Querbes, W., Tam, Y. K., Ansell, S. M., Kumar, V., Qin, J., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.124 · Cited by 625 · see citing works
Self-citationDesigning Chemically Modified Oligonucleotides for Targeted Gene Silencing
Deleavey, G. F., & Damha, M. J. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.07.011 · Cited by 590 · see citing works
Lee, Y. C., Townsend, R. R., Hardy, M. R., Lönngren, J., Arnarp, J., Haraldsson, M., & Lönn, H. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)33240-x · Cited by 503 · see citing works
Grefhorst, A., Elzinga, B. M., Voshol, P. J., Plösch, T., Kok, T., Bloks, V. W., van der Sluijs, F. H., Havekes, L. M., Romijn, J. A., Verkade, H. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204887200 · Cited by 502 · see citing works
The asialoglycoprotein receptor: a model for endocytic transport receptors
Spiess, M. (1990) · Biochemistry · doi:10.1021/bi00495a001 · Cited by 488 · see citing works
Pharmacological Activation of Liver X Receptors Promotes Reverse Cholesterol Transport In Vivo
Naik, S. U., Wang, X., Silva, D., Jaye, M., Macphee, C. H., Reilly, M. P., Billheimer, J. T., Rothblat, G. H., & Rader, D. J. (2005) · Circulation · doi:10.1161/circulationaha.105.560177 · Cited by 379 · see citing works
The LXRs: a new class of oxysterol receptors
Peet, D. J., Janowski, B. A., & Mangelsdorf, D. J. (1998) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(98)80013-0 · Cited by 362 · see citing works
Hepatocyte-targeted RNAi Therapeutics for the Treatment of Chronic Hepatitis B Virus Infection
Wooddell, C. I., Rozema, D. B., Hoßbach, M., John, M., Hamilton, H., Chu, Q., Hegge, J., Klein, J. J., Wakefield, D. H., Oropeza, C. E., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.31 · Cited by 291 · see citing works
Ca2+-dependent carbohydrate-recognition domains in animal proteins
Drickamer, K. (1993) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(05)80112-5 · Cited by 204 · see citing works
Meier, M., Bider, M. D., Malashkevich, V. N., Spiess, M., & Burkhard, P. (2000) · Journal of Molecular Biology · doi:10.1006/jmbi.2000.3853 · Cited by 192 · see citing works
Lönnberg, H. (2009) · Bioconjugate Chemistry · doi:10.1021/bc800406a · Cited by 188 · see citing works
Severgnini, M., Sherman, J., Sehgal, A., Narayanannair, J. K., Aubin, J., Wang, G., Zhang, L., Peng, C. G., Yucius, K., Butler, J. S., et al. (2011) · Cytotechnology · doi:10.1007/s10616-011-9407-0 · Cited by 169 · 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
Grewal, P. K. (2010) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(10)79013-3 · Cited by 136 · see citing works
Glycomimetic Ligands for the Human Asialoglycoprotein Receptor
Mamidyala, S. K., Dutta, S., Chrunyk, B. A., Préville, C., Wang, H., Withka, J. M., McColl, A. S., Subashi, T. A., Hawrylik, S. J., Griffor, M. C., et al. (2012) · Journal of the American Chemical Society · doi:10.1021/ja2104679 · Cited by 105 · see citing works
Receptor-based Targeting of Therapeutics
Mehra, N. K., Mishra, V. K., & Jain, N. K. (2013) · Therapeutic Delivery · doi:10.4155/tde.13.6 · Cited by 97 · see citing works
Reduction of low-density lipoprotein cholesterol by monoclonal antibody inhibition of PCSK9
Stein, E. A., & Raal, F. (2014) · Annual Review of Medicine · doi:10.1146/annurev-med-022613-090402 · Cited by 89 · 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
Oligoribonucleotide Synthesis: The Silyl-Phosphoramidite Method
Damha, M. J., & Ogilvie, K. K. (2003) · Humana Press eBooks · doi:10.1385/0-89603-281-7:81 · Cited by 87 · see citing works
Apolipoprotein E Is Resistant to Intracellular Degradation in Vitro and in Vivo
Rensen, P. C. N., Jong, M. C., van Vark, L. C., van der Boom, H., Hendriks, W. L., van Berkel, T. J. C., Biessen, E. A. L., & Havekes, L. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8564 · Cited by 86 · see citing works
Scotti, E., Calamai, M., Goulbourne, C. N., Zhang, L., Hong, C., Lin, R. R., Choi, J., Pilch, P. F., Fong, L. G., Zou, P., et al. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01716-12 · Cited by 80 · see citing works
Self-citationCalkin, A. C., Goult, B. T., Zhang, L., Fairall, L., Hong, C., Schwabe, J. W. R., & Tontonoz, P. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1111589108 · Cited by 62 · see citing works
Self-citationPourceau, G., Meyer, A., Chevolot, Y., Souteyrand, É., Vasseur, J., & Morvan, F. (2010) · Bioconjugate Chemistry · doi:10.1021/bc1001888 · Cited by 51 · 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
Recent Advances in Active Hepatic Targeting Drug Delivery System
Wang, Y., Du, H., & Zhai, G. (2014) · Current Drug Targets · doi:10.2174/1389450115666140309232100 · Cited by 37 · see citing works
Lowering Plasma Cholesterol by Raising LDL Receptors — Revisited
Young, S. G., & Fong, L. G. (2012) · New England Journal of Medicine · doi:10.1056/nejme1202168 · Cited by 36 · see citing works
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Rupaimoole, R., & Slack, F. J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.246 · Cited by 4,741 · see citing works
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Vargason, A. M., Anselmo, A. C., & Mitragotri, S. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00698-w · Cited by 1,361 · see citing works
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Cabral, H., Miyata, K., Osada, K., & Kataoka, K. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00199 · Cited by 1,309 · see citing works
Overcoming cellular barriers for RNA therapeutics
Dowdy, S. F. (2017) · Nature Biotechnology · doi:10.1038/nbt.3802 · Cited by 1,139 · see citing works
Crooke, S. T., Witztum, J. L., Bennett, C. F., & Baker, B. F. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.004 · Cited by 841 · see citing works
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Raal, F. J., Kallend, D., Ray, K. K., Turner, T., Koenig, W., Wright, R. S., Wijngaard, P. L. J., Curcio, D., Jaros, M. J., Leiter, L. A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1913805 · Cited by 818 · see citing works
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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
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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
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Didiot, M.-C., Hall, L. M., Coles, A. H., Haraszti, R. A., Godinho, B. M., Chase, K., Sapp, E., Ly, S., Alterman, J. F., Hassler, M. R., et al. (2016) · Molecular Therapy · doi:10.1038/mt.2016.126 · Cited by 483 · see citing works
Ray, K. K., Troquay, R. P. T., Visseren, F. L. J., Leiter, L. A., Scott Wright, R., Vikarunnessa, S., Talloczy, Z., Zang, X., Maheux, P., Lesogor, A., et al. (2023) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(22)00353-9 · Cited by 328 · see citing works
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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
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- Authors
- 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., Taneja, N., O’Shea, J., Shaikh, S., Zhang, L., van der Sluis, R. J., Jung, M. E., Akinc, A., Hutabarat, R., Kuchimanchi, S., Fitzgerald, K., Zimmermann, T., van Berkel, T. J. C., Maier, M. A., Rajeev, K. G., & Manoharan, M.
- Affiliations
- Alnylam Pharmaceuticals (United States) (US)
- Alnylam Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts 02142, United States
- Leiden University (NL)
- Division of Biopharmaceutics, Leiden Academic Center for Drug Research, 2300 RA Leiden, The Netherlands
- University of California, Los Angeles (US)
- Corresponding author
- Rajeev, Kallanthottathil G.
- Manoharan, Muthiah
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-12-01
- Volume
- 136
- Issue
- 49
- Pages
- 16958-16961
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2078890343
- Cited by
- 1,141
- References
- 38
- Citations by year
- 2026: 122 · 2025: 112 · 2024: 98 · 2023: 112 · 2022: 99 · 2021: 126 · 2020: 102 · 2019: 86 · 2018: 93 · 2017: 77 · 2016: 68 · 2015: 46
- FWCI
- 26.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- 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
- N-acetylgalactosamine, asialoglycoprotein receptor, hepatocyte targeting, RNA interference, solid-phase oligonucleotide synthesis, subcutaneous administration, chemically modified siRNA
- MeSH terms
- Acetylgalactosamine, Animals, Mice, Inbred C57BL, Molecular Structure, Gene Silencing, Hepatocytes, RNA, Small Interfering, Mice
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