A highly durable RNAi therapeutic inhibitor of PCSK9
Open accessAbstract
BACKGROUND: Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol. METHODS: In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated. RESULTS: The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84). CONCLUSIONS: In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442 .).
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Inclisiran is the first siRNA approved by both US FDA and EMA for the treatment of hypercholesterolemia; subcutaneous injection of a lipid nanoparticle formulation displays high potency in lowering liver PCSK9 and plasma LDL-C levels.
“Inclisiran is the first siRNA approved by both US FDA and EMA for the treatment of hypercholesterolemia; the subcutaneous injection of a lipid nanoparticle formulation of the drug, which specifically binds hepatocyte asialoglycoprotein receptors, displays high potency in lowering liver PCSK9 and plasma LDL-C levels [161,162].”
From The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer’s Disease: A Possible Target for the Disease Treatment (2024) · cites this paper as [161]
The Methods and Discussion report subcutaneous inclisiran and substantial reductions in circulating PCSK9 and LDL cholesterol. The paper describes inclisiran as a carbohydrate-conjugated siRNA, not a lipid-nanoparticle formulation; it identifies the lipid nanoparticle as a different, intravenous agent. It does not establish FDA or EMA approval, and its measured PCSK9 outcome was in plasma rather than liver tissue (page numbers unavailable). (LLM, conf=0.90)
Experimental — accuracy not yet measuredA single subcutaneous injection of trivalent GalNAc-conjugated siRNA can achieve efficacy for >12 months.
“A single subcutaneous injection of trivalent GalNAc-conjugated siRNA can achieve efficacy for >12 months22, 2324.”
From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [22]
The Methods and Results describe a single subcutaneous dose of inclisiran, a triantennary GalNAc-conjugated siRNA, with reductions in PCSK9 and LDL cholesterol maintained at day 180. The paper reports follow-up only to 180 days and discusses potential dosing every 3 or 6 months; it does not establish efficacy beyond 12 months. (LLM, conf=0.90)
Experimental — accuracy not yet measuredA fibrate-induced increase in homocysteine may blunt HDL cholesterol and ApoA1 elevation and may contribute to smaller than estimated benefits of fenofibrate on cardiovascular outcomes.
“However, a fibrate-induced increase in homocysteine may blunt elevation of both HDL-C and ApoA1 levels, and this effect may contribute to the smaller than estimated benefits of fenofibrate in CV outcome parameters [322].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [322]
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Cites
Stone, N. J., Robinson, J. G., Lichtenstein, A. H., Bairey Merz, C. N., Blum, C. B., Eckel, R. H., Goldberg, A. C., Gordon, D., Levy, D., Lloyd-Jones, D. M., et al. (2014) · Circulation · doi:10.1161/01.cir.0000437738.63853.7a · Cited by 7,081 · see citing works
Stone, N. J., Robinson, J. G., Lichtenstein, A. H., Bairey Merz, C. N., Blum, C. B., Eckel, R. H., Goldberg, A. C., Gordon, D., Levy, D., Lloyd-Jones, D. M., et al. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.11.002 · Cited by 3,845 · see citing works
Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events
Robinson, J. G., Farnier, M., Krempf, M., Bergeron, J., Luc, G., Averna, M., Stroes, E. S., Langslet, G., Raal, F. J., El Shahawy, M., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1501031 · Cited by 2,296 · see citing works
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events
Sabatine, M. S., Giugliano, R. P., Wiviott, S. D., Raal, F. J., Blom, D. J., Robinson, J., Ballantyne, C. M., Somaratne, R., Legg, J., Wasserman, S. M., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500858 · Cited by 1,509 · 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-citationTabernero, J. M., Shapiro, G. I., LoRusso, P. M., Cervantes, A. M. R., Schwartz, G. K., Weiss, G. J., Paz-Ares, L. G., Cho, D. C., Infante, J. R., Alsina, M., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0429 · Cited by 700 · see citing works
Self-citationEffect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol
Stein, E. A., Mellis, S., Yancopoulos, G. D., Stahl, N., Logan, D., Smith, W. B., Lisbon, E., Gutierrez, M., Webb, C., Wu, R., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1105803 · Cited by 664 · 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-citationPCSK9: a convertase that coordinates LDL catabolism
Horton, J. D., Cohen, J. C., & Hobbs, H. H. (2008) · Journal of Lipid Research · doi:10.1194/jlr.r800091-jlr200 · Cited by 630 · see citing works
Self-citationZhao, Z., Tuakli-Wosornu, Y., Lagace, T. A., Kinch, L. N., Grishin, N. V., Horton, J. D., Cohen, J. C., & Hobbs, H. H. (2006) · The American Journal of Human Genetics · doi:10.1086/507488 · Cited by 628 · 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
Self-citationGenetic and Metabolic Determinants of Plasma PCSK9 Levels
Lakoski, S. G., Lagace, T. A., Cohen, J. C., Horton, J. D., & Hobbs, H. H. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0141 · Cited by 525 · see citing works
Self-citationNavarese, E. P., Kołodziejczak, M. M., Schulze, V., Gurbel, P. A., Tantry, U. S., Lin, Y., Brockmeyer, M., Kandzari, D. E., Umińska, J. M., D’Agostino, R. B., et al. (2015) · Annals of Internal Medicine · doi:10.7326/m14-2957 · Cited by 404 · see citing works
Koren, M. J., Scott, R. C., Kim, J. B., Knüsel, B., Liu, T., Lei, L., Bolognese, M. A., & Wasserman, S. M. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61771-1 · Cited by 364 · see citing works
The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population
Hooper, A. J., Marais, A. D., Tanyanyiwa, D. M., & Burnett, J. R. (2006) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2006.08.039 · Cited by 363 · see citing works
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events
Sabatine, M. S., Giugliano, R. P., & Wiviott, S. D. (2015) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2015.08.004 · Cited by 360 · see citing works
Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials
Zhang, X.-L., Zhu, Q.-Q., Zhu, L., Chen, J.-Z., Chen, Q.-H., Li, G.-N., Xie, J., Kang, L.-N., & Xu, B. (2015) · BMC Medicine · doi:10.1186/s12916-015-0358-8 · Cited by 260 · see citing works
Roth, E. M., Taskinen, M., Ginsberg, H. N., Kastelein, J. J. P., Colhoun, H. M., Robinson, J. G., Merlet, L., Pordy, R. C., & Baccara‐Dinet, M. T. (2014) · International Journal of Cardiology · doi:10.1016/j.ijcard.2014.06.049 · Cited by 247 · see citing works
Effects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels
Dias, C. S., Shaywitz, A. J., Wasserman, S. M., Smith, B. P., Gao, B., Stolman, D., Crispino, C., Smirnakis, K. V., Emery, M. G., Colbert, A., et al. (2012) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.08.986 · Cited by 230 · see citing works
Ballantyne, C. M., Neutel, J., Cropp, A., Duggan, W. T., Wang, E. Q., Plowchalk, D. R., Sweeney, K., Kaila, N., Vincent, J., & Bays, H. E. (2015) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2015.02.006 · Cited by 170 · see citing works
Jones, P. H., Nair, R., & Thakker, K. M. (2012) · Journal of the American Heart Association · doi:10.1161/jaha.112.001800 · Cited by 119 · see citing works
The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis
Mousavi, S. A., Berge, K. E., & Leren, T. P. (2009) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2009.02167.x · Cited by 112 · see citing works
Egom, E. E. A., & Hafeez, H. (2016) · Advances in clinical chemistry · doi:10.1016/bs.acc.2015.10.005 · Cited by 54 · see citing works
Rouleau, J. L. (2005) · The American Journal of Medicine · doi:10.1016/j.amjmed.2005.09.014 · Cited by 47 · see citing works
Anti-PCSK9 therapies for the treatment of hypercholesterolemia
Hooper, A. J., & Burnett, J. R. (2012) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2012.748743 · Cited by 46 · see citing works
Barkas, F., Liberopoulos, E. N., Kostapanos, M. S., Liamis, G. L., Tziallas, D., & Elisaf, M. (2014) · Angiology · doi:10.1177/0003319714535073 · Cited by 32 · see citing works
Henne, K. R., Ason, B. L., Howard, M., Wang, W., Sun, J., Higbee, J., Tang, J., Matsuda, K. C., Xu, R., Zhou, L., et al. (2015) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.221242 · Cited by 28 · see citing works
Jameson, K., Zhang, Q., Zhao, C., Ramey, D. R., Tershakovec, A. M., Gutkin, S. W., & Marrett, E. (2014) · Current Medical Research and Opinion · doi:10.1185/03007995.2014.890926 · Cited by 13 · see citing works
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Sorted by citations
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz455 · Cited by 8,961 · see citing works
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.08.014 · Cited by 4,854 · see citing works
Advances in oligonucleotide drug delivery
Roberts, T. C., Langer, R., & Wood, M. J. A. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0075-7 · Cited by 2,026 · see citing works
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 chemical evolution of oligonucleotide therapies of clinical utility
Khvorova, A., & Watts, J. K. (2017) · Nature Biotechnology · doi:10.1038/nbt.3765 · Cited by 1,216 · see citing works
Oikonomou, E. K., Marwan, M., Desai, M. Y., Mâncio, J., Alashi, A., Hutt, E., Thomas, S., Herdman, L., Kotanidis, C. P., Thomas, K. E. H., et al. (2018) · The Lancet · doi:10.1016/s0140-6736(18)31114-0 · Cited by 1,193 · 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
Targeting inflammation in atherosclerosis — from experimental insights to the clinic
Soehnlein, O., & Libby, P. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00198-1 · Cited by 1,042 · see citing works
Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol
Ray, K. K., Landmesser, U., Leiter, L. A., Kallend, D., Dufour, R., Karakas, M., Hall, T., Troquay, R. P. T., Turner, T., Visseren, F. L. J., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1615758 · Cited by 992 · see citing works
Self-citationCrooke, 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
Inclisiran 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 · see citing works
Self-citationGalNAc-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 · see citing works
LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation
Ahn, G., Banik, S. M., Miller, C. L., Riley, N. M., Cochran, J. R., & Bertozzi, C. R. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00770-1 · Cited by 654 · see citing works
Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs
Shen, X., & Corey, D. R. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx1239 · Cited by 639 · see citing works
Lipid nanoparticles enabling gene therapies: from concepts to clinical utility
Kulkarni, J. A., Cullis, P. R., & van der Meel, R. (2018) · Nucleic Acid Therapeutics · doi:10.1089/nat.2018.0721 · Cited by 592 · 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
siRNA: Mechanism of action, challenges, and therapeutic approaches
Alshaer, W., Zureigat, H., Alkaraki, A., Al-Kadash, A., Gharaibeh, L. F., Hatmal, M. M., Aljabali, A. A. A., & Awidi, A. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174178 · Cited by 450 · see citing works
Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?
Engelen, S. E., Robinson, A., Zurke, Y.-X., & Monaco, C. G. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00668-4 · Cited by 442 · see citing works
Liver fibrosis: Direct antifibrotic agents and targeted therapies
Schuppan, D., Ashfaq–Khan, M., Yang, A. T., & Kim, Y. O. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.04.006 · Cited by 440 · 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
Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives
Poller, W. C., Dimmeler, S., Heymans, S. R. B., Zeller, T., Haas, J., Karakas, M., Leistner, D. M., Jakob, P., Nakagawa, S., Blankenberg, S., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx165 · Cited by 412 · see citing works
RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges
Yu, A., Choi, Y. H., & Tu, M. (2020) · Pharmacological Reviews · doi:10.1124/pr.120.019554 · Cited by 405 · see citing works
Delivery of oligonucleotide‐based therapeutics: challenges and opportunities
Hammond, S. M., Aartsma-Rus, A. M., Alves, S., Borgos, S. E., Buijsen, R. A. M., Collin, R. W. J., Covello, G., Denti, M. A., Desviat, L. R., Echevarría, L., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202013243 · Cited by 395 · see citing works
Recent advances in siRNA delivery mediated by lipid-based nanoparticles
Yonezawa, S., Koide, H., & Asai, T. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.07.022 · Cited by 386 · see citing works
Lamb, Y. N. (2021) · Drugs · doi:10.1007/s40265-021-01473-6 · Cited by 375 · see citing works
Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials
Shi, Y., Zhang, H., Huang, S., Yin, L., Wang, F., Luo, P., & Huang, H. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01055-2 · Cited by 366 · see citing works
PCSK9 inhibitors: clinical evidence and implementation
Sabatine, M. S. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0107-8 · Cited by 363 · see citing works
Diversity and inclusion in genomic research: why the uneven progress?
Bentley, A. R., Callier, S., & Rotimi, C. N. (2017) · Journal of Community Genetics · doi:10.1007/s12687-017-0316-6 · Cited by 357 · see citing works
Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling
Softic, S., Gupta, M. K., Wang, G.-X., Fujisaka, S., O'Neill, B. T., Rao, T. N., Willoughby, J. L. S., Harbison, C. E., Fitzgerald, K. J., Ilkayeva, O., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci94585 · Cited by 349 · see citing works
Self-citationDyslipidaemia in nephrotic syndrome: mechanisms and treatment
Agrawal, S., Zaritsky, J. J., Fornoni, A., & Smoyer, W. E. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2017.155 · Cited by 337 · 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
Therapeutic Oligonucleotides: State of the Art
Smith, C. I. E., & Zain, R. (2018) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021050 · Cited by 327 · see citing works
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 · 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
Precise RNA editing by recruiting endogenous ADARs with antisense oligonucleotides
Merkle, T., Merz, S. K., Reautschnig, P., Blaha, A., Li, Q., Vogel, P., Wettengel, J., Li, J. B., & Stafforst, T. (2019) · Nature Biotechnology · doi:10.1038/s41587-019-0013-6 · Cited by 299 · see citing works
Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance
Ghorpade, D. S., Özcan, L., Zheng, Z., Nicoloro, S. M. C., Shen, Y., Chen, E., Blüher, M., Czech, M., & Tabas, I. A. (2018) · Nature · doi:10.1038/nature26138 · Cited by 295 · see citing works
Lauffer, M. C., van Roon‐Mom, W., Aartsma-Rus, A. M., & Collaborative, N. =. 1. (2024) · Communications Medicine · doi:10.1038/s43856-023-00419-1 · Cited by 289 · see citing works
RNAi therapeutic and its innovative biotechnological evolution
Weng, Y., Xiao, H., Zhang, J., Liang, X., & Huang, Y. (2019) · Biotechnology Advances · doi:10.1016/j.biotechadv.2019.04.012 · Cited by 288 · 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
Treating Disease at the RNA Level with Oligonucleotides
Levin, A. A. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1705346 · Cited by 280 · see citing works
The powerful world of antisense oligonucleotides: From bench to bedside
Quéméner, A. M., Bachelot, L., Forestier, A., Donnou‐Fournet, E., Gilot, D., & Galibert, M. (2020) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1594 · Cited by 279 · 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-citationLipid management in patients with chronic kidney disease
Ferro, C. J., Mark, P. B., Kanbay, M., Sarafidis, P. A., Heine, G. H., Rossignol, P., Massy, Z. A., Mallamaci, F., Valdivielso, J. M., Małyszko, J., et al. (2018) · Nature Reviews Nephrology · doi:10.1038/s41581-018-0072-9 · Cited by 275 · see citing works
Goeller, M., Tamarappoo, B. K., Kwan, A. C., Cadet, S. J., Commandeur, F., Razipour, A., Slomka, P. J., Gransar, H., Chen, X., Otaki, Y., et al. (2019) · European Heart Journal - Cardiovascular Imaging · doi:10.1093/ehjci/jez013 · Cited by 249 · see citing works
Lee, R. G., Mazzola, A. M., Braun, M. C., Platt, C., Vafai, S. B., Kathiresan, S., Rohde, E., Bellinger, A. M., & Khera, A. V. (2022) · Circulation · doi:10.1161/circulationaha.122.062132 · Cited by 249 · see citing works
The Multifaceted Biology of PCSK9
Seidah, N. G., & Prat, A. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab035 · Cited by 232 · see citing works
An RNA toolbox for cancer immunotherapy
Pastor, F., Berraondo, P., Etxeberria, I., Frederick, J., Sahin, U., Gilboa, E., & Melero, I. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.132 · Cited by 229 · see citing works
Alterman, J. F., Godinho, B. M. D. C., Hassler, M. R., Ferguson, C. M., Echeverria, D., Sapp, E., Haraszti, R. A., Coles, A. H., Conroy, F., Miller, R., et al. (2019) · Nature Biotechnology · doi:10.1038/s41587-019-0205-0 · Cited by 227 · see citing works
2023 Chinese guideline for lipid management
Li, J., Zhao, S., Zhao, D. H., Lü, G., Peng, D., Liu, J., Chen, Z., Guo, Y., Wu, N., Yan, S.-K., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1190934 · Cited by 227 · 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-citationRNAi modulation of placental sFLT1 for the treatment of preeclampsia
Turanov, A. A., Lo, A. S., Hassler, M. R., Makris, A., Ashar-Patel, A., Alterman, J. F., Coles, A. H., Haraszti, R. Á., Roux, L., Godinho, B. M. D. C., et al. (2018) · Nature Biotechnology · doi:10.1038/nbt.4297 · Cited by 212 · see citing works
Imaging small molecule-induced endosomal escape of siRNA
Rietz, H. D., Hedlund, H., Wilhelmson, S., Nordenfelt, P., & Wittrup, A. (2020) · Nature Communications · doi:10.1038/s41467-020-15300-1 · Cited by 203 · see citing works
Familial hypercholesterolemia treatments: Guidelines and new therapies
Raal, F. J., Hovingh, G. K., & Catapano, A. L. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.06.859 · Cited by 198 · see citing works
Myocardial Infarction—From Atherosclerosis to Thrombosis
Palasubramaniam, J., Wang, X., & Peter, K. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.312578 · Cited by 196 · see citing works
Wahane, A. V., Waghmode, A., Kapphahn, A., Dhuri, K., Gupta, A., & Bahal, R. (2020) · Molecules · doi:10.3390/molecules25122866 · Cited by 196 · see citing works
Tapping the RNA world for therapeutics
Lieberman, J. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0054-4 · Cited by 195 · see citing works
Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): From bench to bedside
Bao, X., Liang, Y., Chang, H., Cai, T., Feng, B., Gordon, K., Zhu, Y., Shi, H., He, Y., & Xie, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01690-3 · Cited by 187 · see citing works
Zhang, J., Chen, B., Gan, C., Sun, H., Zhang, J., & Feng, L. (2023) · International Journal of Nanomedicine · doi:10.2147/ijn.s436038 · Cited by 186 · 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
Self-citationPCSK9 Biology and Its Role in Atherothrombosis
Barale, C., Melchionda, E., Morotti, A., & Russo, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115880 · Cited by 176 · see citing works
RNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors
Thakore, P. I., Kwon, J. B., Nelson, C. E., Rouse, D. C., Gemberling, M. P., Oliver, M. L., & Gersbach, C. A. (2018) · Nature Communications · doi:10.1038/s41467-018-04048-4 · Cited by 173 · see citing works
Antisense oligonucleotides: a novel Frontier in pharmacological strategy
Collotta, D., Bertocchi, I., Chiapello, E., & Collino, M. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1304342 · Cited by 173 · see citing works
Dzau, V. J., & Balatbat, C. (2019) · Hypertension · doi:10.1161/hypertensionaha.119.13437 · Cited by 171 · see citing works
Cardiovascular Gene Therapy: Past, Present, and Future
Ylä‐Herttuala, S., & Baker, A. H. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2017.03.027 · Cited by 166 · see citing works
Translational Challenges in Atrial Fibrillation
Heijman, J., Guichard, J.-B., Dobrev, D., & Nattel, S. (2018) · Circulation Research · doi:10.1161/circresaha.117.311081 · Cited by 165 · see citing works
Jawi, M., Frohlich, J. J., & Chan, S. (2020) · Journal of Lipids · doi:10.1155/2020/3491764 · Cited by 164 · see citing works
Reshke, R., Taylor, J. A., Savard, A., Guo, H., Rhym, L. H., Kowalski, P. S., Trung, M. T., Campbell, C. M., Little, W., Anderson, D. G., et al. (2020) · Nature Biomedical Engineering · doi:10.1038/s41551-019-0502-4 · Cited by 163 · see citing works
Myotoxicity of statins: Mechanism of action
du Souich, P., Roederer, G. O., & Dufour, R. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.029 · Cited by 162 · see citing works
Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?
Dowdy, S. F. (2023) · RNA · doi:10.1261/rna.079507.122 · Cited by 160 · see citing works
Wright, R. S., Collins, M. G., Stoekenbroek, R. M., Robson, R. A., Wijngaard, P. L. J., Landmesser, U., Leiter, L. A., Kastelein, J. J. P., Ray, K. K., & Kallend, D. G. (2019) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2019.08.021 · Cited by 158 · see citing works
Self-citationDelivery of RNA Therapeutics: The Great Endosomal Escape!
Dowdy, S. F., Setten, R. L., Cui, X.-S., & Jadhav, S. G. (2022) · Nucleic Acid Therapeutics · doi:10.1089/nat.2022.0004 · Cited by 158 · 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
Nanoparticle Therapy for Vascular Diseases
Flores, A. M., Ye, J., Jarr, K.-U., Hosseini-Nassab, N., Smith, B. R., & Leeper, N. J. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.311569 · Cited by 152 · see citing works
Addressing dyslipidemic risk beyond LDL-cholesterol
Tall, A. R., Thomas, D. G., Gonzalez-Cabodevilla, A. G., & Goldberg, I. J. (2022) · Journal of Clinical Investigation · doi:10.1172/jci148559 · Cited by 150 · see citing works
Advances in lipid-lowering therapy through gene-silencing technologies
Nordestgaard, B. G., Nicholls, S. J., Langsted, A., Ray, K. K., & Tybjærg‐Hansen, A. (2018) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2018.3 · Cited by 147 · see citing works
Osborn, M. F., Coles, A. H., Biscans, A., Haraszti, R. Á., Roux, L., Davis, S. M., Ly, S., Echeverria, D., Hassler, M. R., Godinho, B. M. D. C., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1232 · Cited by 147 · see citing works
Triple‐Targeting Delivery of CRISPR/Cas9 To Reduce the Risk of Cardiovascular Diseases
Zhang, L., Wang, L., Xie, Y., Wang, P., Deng, S., Qin, A., Zhang, J., Yu, X., Zheng, W., & Jiang, X. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201903618 · Cited by 144 · see citing works
Inhibiting PCSK9 — biology beyond LDL control
Stoekenbroek, R. M., Lambert, G., Cariou, B., & Hovingh, G. K. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0110-5 · Cited by 141 · see citing works
Small interfering RNA: Discovery, pharmacology and clinical development—An introductory review
Ranasinghe, P., Addison, M. L., Dear, J. W., & Webb, D. J. (2023) · British Journal of Pharmacology · doi:10.1111/bph.15972 · Cited by 138 · see citing works
Improving siRNA Delivery <i>In Vivo</i> Through Lipid Conjugation
Osborn, M. F., & Khvorova, A. (2018) · Nucleic Acid Therapeutics · doi:10.1089/nat.2018.0725 · Cited by 137 · 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
5΄-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo
Haraszti, R. Á., Roux, L., Coles, A. H., Turanov, A. A., Alterman, J. F., Echeverria, D., Godinho, B. M. D. C., D, N. A. M., & Khvorova, A. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx507 · Cited by 128 · see citing works
Effective tools for RNA-derived therapeutics: siRNA interference or miRNA mimicry
Wang, P., Zhou, Y., & Richards, M. (2021) · Theranostics · doi:10.7150/thno.62642 · Cited by 123 · see citing works
Inclisiran—New hope in the management of lipid disorders?
Dyrbuś, K., Gąsior, M., Penson, P., Ray, K. K., & Banach, M. (2020) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2019.11.001 · Cited by 120 · see citing works
Kabir, T. D., Ganda, C., Brown, R. A. M., Beveridge, D. J., Richardson, K. L., Chaturvedi, V., Candy, P. A., Epis, M. R., Wintle, L. C., Kalinowski, F. C., et al. (2017) · Hepatology · doi:10.1002/hep.29478 · Cited by 120 · see citing works
Translational Perspective on Epigenetics in Cardiovascular Disease
van der Harst, P., Windt, L. J. D., & Chambers, J. C. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.05.067 · Cited by 117 · see citing works
Cardiovascular Precision Medicine in the Genomics Era
Dainis, A., & Ashley, E. A. (2018) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2018.01.003 · Cited by 117 · see citing works
Meschia, J. F., & Brott, T. G. (2017) · European Journal of Neurology · doi:10.1111/ene.13409 · Cited by 117 · see citing works
2023 China Guidelines for Lipid Management
Li, J., Zhao, S., Zhao, D., Lü, G., Peng, D., Liu, J., Chen, Z., Guo, Y., Wu, N., Yan, S.-K., et al. (2023) · 老年心脏病学杂志：英文版 · doi:10.26599/1671-5411.2023.09.008 · Cited by 116 · see citing works
Small Interfering RNA Therapeutic Inclisiran: A New Approach to Targeting PCSK9
German, C. A., & Shapiro, M. D. (2019) · BioDrugs · doi:10.1007/s40259-019-00399-6 · Cited by 115 · see citing works
All-in-one adeno-associated virus delivery and genome editing by Neisseria meningitidis Cas9 in vivo
Ibraheim, R., Song, C., Mir, A., Amrani, N., Xue, W., & Sontheimer, E. J. (2018) · Genome biology · doi:10.1186/s13059-018-1515-0 · Cited by 110 · see citing works
New and Emerging Therapies for Reduction of LDL-Cholesterol and Apolipoprotein B
Nurmohamed, N. S., Návar, A. M., & Kastelein, J. J. P. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2020.11.079 · Cited by 110 · see citing works
Lipids and lipoproteins in cardiovascular diseases: a classification
Bhargava, S., de la Puente-Secades, S., Schurgers, L. J., & Jankowski, J. (2022) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2022.02.001 · Cited by 110 · 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/s10557-019-06919-4 · Cited by 110 · see citing works
Self-citationCurrent Challenges in Delivery and Cytosolic Translocation of Therapeutic RNAs
Johannes, L., & Lucchino, M. (2018) · Nucleic Acid Therapeutics · doi:10.1089/nat.2017.0716 · Cited by 108 · see citing works
Optimized Cholesterol-siRNA Chemistry Improves Productive Loading onto Extracellular Vesicles
Haraszti, R. Á., Miller, R., Didiot, M.-C., Biscans, A., Alterman, J. F., Hassler, M. R., Roux, L., Echeverria, D., Sapp, E., DiFiglia, M., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.05.024 · Cited by 106 · see citing works
Inclisiran for the Treatment of Cardiovascular Disease: the Orion Clinical Development Program
Stoekenbroek, R. M., Kallend, D. G., Wijngaard, P. L. J., & Kastelein, J. J. P. (2018) · Future Cardiology · doi:10.2217/fca-2018-0067 · Cited by 106 · see citing works
Self-citationSignaling cascades in the failing heart and emerging therapeutic strategies
He, X., Du, T., Long, T., Liao, X., Dong, Y., & Huang, Z. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00972-6 · Cited by 105 · see citing works
Das, S., Shah, R. V., Dimmeler, S., Freedman, J. E., Holley, C. L., Lee, J., Moore, K. J., Musunuru, K., Wang, D., Xiao, J., et al. (2020) · Circulation Genomic and Precision Medicine · doi:10.1161/hcg.0000000000000062 · Cited by 104 · see citing works
Three ‘E’ challenges for siRNA drug development
Guo, S., Zhang, M., & Huang, Y. (2023) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.10.005 · Cited by 104 · see citing works
- Authors
- Fitzgerald, K., White, S., Borodovsky, A., Bettencourt, B. R., Strahs, A., Clausen, V., Wijngaard, P., Horton, J. D., Taubel, J., Brooks, A., Fernando, C., Kauffman, R. S., Kallend, D., Vaishnaw, A., & Simon, A.
- Affiliations
- Alnylam Pharmaceuticals (United States) (US)
- St George's, University of London (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-01-05
- Volume
- 376
- Issue
- 1
- Pages
- 41-51
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5778873
- OpenAlex
- W2555483953
- Cited by
- 768
- References
- 29
- Citations by year
- 2026: 43 · 2025: 61 · 2024: 84 · 2023: 89 · 2022: 85 · 2021: 68 · 2020: 88 · 2019: 76 · 2018: 95 · 2017: 74 · 2016: 3 · 2013: 1
- FWCI
- 91.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL020948)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- inclisiran, PCSK9 inhibition, RNA interference therapy, LDL cholesterol lowering, hypercholesterolemia, statin therapy, pharmacokinetics, pharmacodynamics, safety, multiple-dose regimen, single ascending dose, healthy volunteers, lipid-lowering drugs, hypertriglyceridemia, hyperuricemia
- MeSH terms
- RNAi Therapeutics, Proprotein Convertase 9, PCSK9 Inhibitors, Acetylgalactosamine, Adolescent, Adult, Aged, Anticholesteremic Agents, Female, Humans, Injections, Subcutaneous, Cholesterol, LDL, Male, Middle Aged, Single-Blind Method, RNA, Small Interfering, RNA-Induced Silencing Complex, Young Adult, Healthy Volunteers
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