The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
Therapeutic siRNA: State-of-the-Art and Future Perspectives
Open accessAbstract
The highly specific induction of RNA interference-mediated gene knockdown, based on the direct application of small interfering RNAs (siRNAs), opens novel avenues towards innovative therapies. Two decades after the discovery of the RNA interference mechanism, the first siRNA drugs received approval for clinical use by the US Food and Drug Administration and the European Medicines Agency between 2018 and 2022. These are mainly based on an siRNA conjugation with a targeting moiety for liver hepatocytes, N-acetylgalactosamine, and cover the treatment of acute hepatic porphyria, transthyretin-mediated amyloidosis, hypercholesterolemia, and primary hyperoxaluria type 1. Still, the development of siRNA therapeutics faces several challenges and issues, including the definition of optimal siRNAs in terms of target, sequence, and chemical modifications, siRNA delivery to its intended site of action, and the absence of unspecific off-target effects. Further siRNA drugs are in clinical studies, based on different delivery systems and covering a wide range of different pathologies including metabolic diseases, hematology, infectious diseases, oncology, ocular diseases, and others. This article reviews the knowledge on siRNA design and chemical modification, as well as issues related to siRNA delivery that may be addressed using different delivery systems. Details on the mode of action and clinical status of the various siRNA therapeutics are provided, before giving an outlook on issues regarding the future of siRNA drugs and on their potential as one emerging standard modality in pharmacotherapy. Notably, this may also cover otherwise un-druggable diseases, the definition of non-coding RNAs as targets, and novel concepts of personalized and combination treatment regimens.
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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
Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
Adams, D., Gonzalez-Duarte, A., O’Riordan, W. D., Yang, C.-C., Ueda, M., Kristen, A. V., Tournev, I., Schmidt, H. H., Coelho, T., Berk, J. L., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1716153 · Cited by 3,047
Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer
Kamerkar, S., LeBleu, V. S., Sugimoto, H., Yang, S., Ruivo, C. F., Melo, S. A., Lee, J. J., & Kalluri, R. (2017) · Nature · doi:10.1038/nature22341 · Cited by 2,639
Rational siRNA design for RNA interference
Reynolds, A., Leake, D., Boese, Q., Scaringe, S., Marshall, W. S., & Khvorova, A. (2004) · Nature Biotechnology · doi:10.1038/nbt936 · Cited by 2,094
Ketting, R. F., Fischer, S. E. J., Bernstein, E., Sijen, T., Hannon, G. J., & Plasterk, R. H. A. (2001) · Genes & Development · doi:10.1101/gad.927801 · Cited by 1,852
Rational design of cationic lipids for siRNA delivery
Semple, S. C., Akinc, A., Chen, J., Sandhu, A. P., Mui, B. L., Cho, C. K., Sah, D. W. Y., Stebbing, D., Crosley, E. J., Yaworski, E., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1602 · Cited by 1,822 · cited 8×
“Other drawbacks of nanoparticles such as LNPs include that it is often necessary to administer them intravenously, making it a comparatively complex process that is unfavorable for patients.”
BackgroundInfluentialDelivery materials for siRNA therapeutics
Kanasty, R., Dorkin, J. R., Vegas, A., & Anderson, D. (2013) · Nature Materials · doi:10.1038/nmat3765 · Cited by 1,800
Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol
Ray, K. K., Wright, R. S., Kallend, D., Koenig, W., Leiter, L. A., Raal, F. J., Bisch, J. A., Richardson, T., Jaros, M., Wijngaard, P. L. J., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1912387 · Cited by 1,665
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
The current state and future directions of RNAi-based therapeutics
Setten, R. L., Rossi, J. J., & Han, S.-P. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0017-4 · Cited by 1,443
Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo
Jayaraman, M., Ansell, S. M., Mui, B. L., Tam, Y. K., Chen, J., Du, X., Butler, D., Eltepu, L., Matsuda, S., Narayanannair, J. K., et al. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201203263 · Cited by 1,267
Overcoming cellular barriers for RNA therapeutics
Dowdy, S. F. (2017) · Nature Biotechnology · doi:10.1038/nbt.3802 · Cited by 1,139
siRNA versus miRNA as therapeutics for gene silencing
Lam, J. K. W., Chow, M. Y. T., Zhang, Y., & Leung, S. W. S. (2015) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2015.23 · Cited by 1,081
Overview of complement activation and regulation
Noris, M., & Remuzzi, G. (2013) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2013.08.001 · Cited by 864 · cited 1×
“It is under development for the treatment of life-threatening rare complement-mediated diseases [132], including paroxysmal nocturnal hemoglobinuria, immunoglobulin A nephropathy, atypical hemolytic uremic syndrome, and generalized myasthenia gravis.”
BackgroundInclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia
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
Rother, R. P., Rollins, S. A., Mojcik, C. F., Brodsky, R. A., & Bell, L. (2007) · Nature Biotechnology · doi:10.1038/nbt1344 · Cited by 778 · cited 1×
“Consequently, the formation of the membrane attack complex and the release of the C5a anaphylatoxin are prevented [133, 134].”
BackgroundA 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
GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics
Springer, A. D., & Dowdy, S. F. (2018) · Nucleic Acid Therapeutics · doi:10.1089/nat.2018.0736 · Cited by 711
Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown
Wittrup, A., Ai, A., Liu, X., Hamar, P., Trifonova, R., Charisse, K., Manoharan, M., Kirchhausen, T., & Lieberman, J. (2015) · Nature Biotechnology · doi:10.1038/nbt.3298 · Cited by 693
Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria
Balwani, M., Sardh, E., Ventura, P., Peiró, P. A., Rees, D. C., Stölzel, U., Bissell, D. M., Bonkovsky, H. L., Windyga, J., Anderson, K. E., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1913147 · Cited by 608
Golan, T., Khvalevsky, E. Z., Hubert, A., Gabai, R. M., Hen, N., Segal, A., Domb, A., Harari, G., David, E. B., Raskin, S., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4183 · Cited by 336
Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates
Foster, D. J., Brown, C. R., Shaikh, S., Trapp, C., Schlegel, M. K., Qian, K., Sehgal, A., Rajeev, K. G., Jadhav, V., Manoharan, M., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2017.12.021 · Cited by 325
From the RNA world to the clinic
Sullenger, B. A., & Nair, S. (2016) · Science · doi:10.1126/science.aad8709 · Cited by 274
The UCSC Genome Browser database: 2022 update
Lee, B. T., Barber, G. P., Benet-Pagès, A., Casper, J., Clawson, H., Diekhans, M., Fischer, C., Gonzalez, J. N., Hinrichs, A. S., Lee, C. M., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkab959 · Cited by 273
Lekka, E., & Hall, J. (2018) · FEBS Letters · doi:10.1002/1873-3468.13182 · Cited by 251
Thielmann, M., Corteville, D., Szabo, G., Swaminathan, M., Lamy, A., Lehner, L. J., Brown, C. D., Noiseux, N., Atta, M. G., Squiers, E. C., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.053029 · Cited by 97
Dutta, C., Avitahl-Curtis, N., Pursell, N., Larsson Cohen, M., Holmes, B., Diwanji, R., Zhou, W., Apponi, L., Koser, M., Ying, B., et al. (2016) · Molecular Therapy · doi:10.1038/mt.2016.4 · Cited by 81
Cited by
Harnessing RNA Interference for Cholesterol Lowering: The Bench‐to‐Bedside Story of Inclisiran
Wilkinson, M. J., Bajaj, A., Brousseau, M. E., & Taub, P. R. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.123.032031 · Cited by 37
GalNac-siRNA conjugate delivery technology promotes the treatment of typical chronic liver diseases
Qin, Z.-X., Zuo, L., Zeng, Z., Ma, R., Xie, W., Zhu, X., & Zhou, X. (2025) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2025.2466767 · Cited by 32
Targeting PCSK9 With Antibodies and Gene Silencing to Reduce LDL Cholesterol
Newman, C. B., & Tobert, J. A. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac708 · Cited by 20
Metadata
- Authors
- Friedrich, M., & Aigner, A.
- Venue
- BioDrugs
- Published
- 2022-08-23
- Volume
- 36
- Issue
- 5
- Pages
- 549-571
- ISSN
- 1172-7039 (ISSN-L)
- 1173-8804
- 1179-190X
- OpenAlex
- W4292702578
- Cited by
- 396
- References
- 27
- FWCI
- 21.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
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