The DOI matches its Crossref record; 31 of the 32 references it cites were found in a registry or an index.
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 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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“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]
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“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]
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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
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
Hannon, G. J. (2002) · Nature · doi:10.1038/418244a · Cited by 3,651
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
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
Self-citationsiRNA function in RNAi: A chemical modification analysis
Chiu, Y., & Rana, T. M. (2003) · RNA · doi:10.1261/rna.5103703 · Cited by 863
Knocking down disease: a progress report on siRNA therapeutics
Wittrup, A., & Lieberman, J. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3978 · Cited by 827
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
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 644
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 586
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Items 301–327 of 327
Vogler, J., Ambike, S. S., Velkov, S., Cheng, C., Neubecker, P., Fischhaber, N., Mallick, P., Martan, I., Sauerhering, L., von Brunn, A., et al. (2026) · Genome Medicine · doi:10.1186/s13073-026-01659-1
Rational Design and Screening of Chemically Modified Anti-SARS-CoV-2 siRNA
Cheng, Z., Cai, Y., Zhang, E., Cheng, Y., Li, Y., Zhang, X., Liang, G., Hou, M., Wang, C., Hu, T., et al. (2026) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.6c00095
Larsen, A. W., Braun, J., Rotrattanadumrong, R., Berninger, P., Yonchev, D., Gagneur, J., Butnaru, D., & Marsico, A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.13.732049
Chandran, V. I., Christiansen, S. H., Hansen, S. M., Larsen, A.-N., Præstholm, S. M., Toft, N. I., Palarasah, Y., Skytthe, M. K., Moestrup, S. K., Grøntved, L., et al. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2026.153145
Hou, Y., Xing, Y., Chen, C., Su, D., Zhou, Z., Ye, Y., Lai, Z., Peng, Z., Cai, H., Sun, M., et al. (2026) · Leukemia · doi:10.1038/s41375-026-03014-0
RNA interference: Mechanisms and therapeutic applications
Datta, N., Karmakar, K., & Vinchurkar, K. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-40620-1.00018-2
Michler, T., Kosinska, A. D., Merdan, O., Hagen, P., Bunse, T., Öz, E. A., Su, J., Busch, D. H., Mogler, C., & Protzer, U. (2026) · JHEP Reports · doi:10.1016/j.jhepr.2026.101943
Ahn, C., Jeong, H., Yim, H. W., Kim, N. J., Han, S., & Oh, I. (2026) · Frontiers in Drug Safety and Regulation · doi:10.3389/fdsfr.2026.1855572
Tan, W. C., Dong, Y., Shi, Y., Chen, N., Ye, S., Zhang, H., Chen, P., Zuo, Y., & Du, H. (2026) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2026.103029
Ueda, K., Sato, T., Sasaki, J., Hashiba, K., Mizuno, T., Yamada, H., & Sugimoto, M. (2026) · Nucleic Acid Therapeutics · doi:10.1177/21593337261469503
Qasim, M., Naaz, S., Pratihar, S., Sharma, S. N., & Sinha, S. (2026) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.6c00176
Nogi, Y., Tsukimoto, J., Saito–Tarashima, N., Koma, T., Nomaguchi, M., & Minakawa, N. (2026) · Chemistry - A European Journal · doi:10.1002/chem.71507
Jawaria, Noor, A., Zarlashat, Y., Khan, M. E. A., Loureiro, E. M., & Dósa, E. (2026) · Life · doi:10.3390/life16081301
Zhang, X., Zhang, X., Yang, Q., Kang, B., Dan, M., Li, C., Chen, Y., Gan, J., & Su, X. (2026) · Molecular Therapy · doi:10.1016/j.ymthe.2026.08.022
Meng, Q., Wang, X., Zhang, Y., Pushpakom, S. P., Yang, J., Feng, H., & Wang, M. (2026) · PLoS ONE · doi:10.1371/journal.pone.0354751
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Cai, Y., Hou, Q., Cheng, Z., Cheng, Y., Zhang, E., Li, Y., Zhang, X., Wang, C., Hu, T., Tian, G., et al. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110526
Therapeutic oligonucleotides as genetic medicines: The current state and future perspective
Godinho, B. M. D. C., Ferguson, C. M., & Aartsma-Rus, A. M. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2026.103058
Congenital Long QT Syndrome: From Conventional Management to Emerging Biological Therapies
Liu, Q., Wang, Y., Zhang, P., & Lv, T. (2026) · Reviews in Cardiovascular Medicine · doi:10.31083/rcm51843
Lee, C. H., Moon, H., Lee, K. H., Na, J. H., Choi, J. U., Choi, J. W., & Lee, S. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.115431
Afandizada, Y., Memmedov, H., Orujov, M., Eyvazova, S., & Amikishiyev, S. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1950465
Andersen, H. M., Bell, A., Hill, R. C., Murphy, A., Huskin, M., Mohutsky, M. A., & Wiethoff, C. M. (2026) · Drug Metabolism and Disposition · doi:10.1016/j.dmd.2026.100415
Zhang, E., Zheng, W., LI, Y., Cheng, Z., Cai, Y., Cheng, Y., Zhang, X., Hou, Q., Liu, Y., Bingxue, M., et al. (2026) · Journal of drug targeting · doi:10.1080/1061186x.2026.2721709
siRNA therapeutics: from hepatic delivery to extrahepatic targeting
Wang, N., Meng, L., Shi, J.-X., & Bartneck, M. (2026) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2026.2754564
BindingDB (2022) · UC San Diego · doi:10.7270/q2542s7z
Metadata
- 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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