The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates
Open accessAbstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low density lipoprotein receptor (LDLR) protein levels and function. Loss of PCSK9 increases LDLR levels in liver and reduces plasma LDL cholesterol (LDLc), whereas excess PCSK9 activity decreases liver LDLR levels and increases plasma LDLc. Here, we have developed active, cross-species, small interfering RNAs (siRNAs) capable of targeting murine, rat, nonhuman primate (NHP), and human PCSK9. For in vivo studies, PCSK9 and control siRNAs were formulated in a lipidoid nanoparticle (LNP). Liver-specific siRNA silencing of PCSK9 in mice and rats reduced PCSK9 mRNA levels by 50–70%. The reduction in PCSK9 transcript was associated with up to a 60% reduction in plasma cholesterol concentrations. These effects were shown to be mediated by an RNAi mechanism, using 5′-RACE. In transgenic mice expressing human PCSK9, siRNAs silenced the human PCSK9 transcript by >70% and significantly reduced PCSK9 plasma protein levels. In NHP, a single dose of siRNA targeting PCSK9 resulted in a rapid, durable, and reversible lowering of plasma PCSK9, apolipoprotein B, and LDLc, without measurable effects on either HDL cholesterol (HDLc) or triglycerides (TGs). The effects of PCSK9 silencing lasted for 3 weeks after a single bolus i.v. administration. These results validate PCSK9 targeting with RNAi therapeutics as an approach to specifically lower LDLc, paving the way for the development of PCSK9-lowering agents as a future strategy for treatment of hypercholesterolemia.
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Citations
Cites
Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease
Cohen, J. C., Boerwinkle, E., Mosley, T. H., & Hobbs, H. H. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa054013 · Cited by 3,181
Schwartz, G. G. (2001) · JAMA · doi:10.1001/jama.285.13.1711 · Cited by 2,499
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
RNAi-mediated gene silencing in non-human primates
Zimmermann, T. S., Lee, A. C. H., Akinc, A., Bramlage, B., Bumcrot, D., Fedoruk, M. N., Harborth, J., Heyes, J. A., Jeffs, L. B., John, M., et al. (2006) · Nature · doi:10.1038/nature04688 · Cited by 1,357 · cited 1×
“To confirm that the reduction in PCSK9 transcript observed in rodents was because of a siRNA mechanism, liver extracts from either treated or control rats were subjected to rapid amplification of cDNA ends (5 -RACE), a method previously used to demonstrate that siRNA-mediated cleavage occurs (21, 22).”
MethodSecreted PCSK9 decreases the number of LDL receptors in hepatocytes and inlivers of parabiotic mice
Lagace, T. A., Curtis, D. E., Garuti, R., McNutt, M. C., Park, S. W., Prather, H. B., Anderson, N. N., Ho, Y. K., Hammer, R. E., & Horton, J. D. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29383 · Cited by 681
Self-citationIbdah, J. A., Perlegas, P., Zhao, Y., Angdisen, J., Borgerink, H., Shadoan, M. K., Wagner, J. D., Matern, D., Rinaldo, P., & Cline, J. M. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.02.001 · Cited by 186
Cited by
Knocking down barriers: advances in siRNA delivery
Whitehead, K. A., Langer, R., & Anderson, D. G. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2742 · Cited by 3,115
Self-citationRational 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
Self-citationGilleron, J., Querbes, W., Zeigerer, A., Borodovsky, A., Marsico, G., Schubert, U., Manygoats, K., Seifert, S., Andree, C., Stöter, M., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2612 · Cited by 1,681
Self-citationTargeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms
Akinc, A., Querbes, W., De, S., Qin, J., Frank-Kamenetsky, M., Jayaprakash, K. N., Jayaraman, M., Rajeev, K. G., Cantley, W. L., Dorkin, J. R., et al. (2010) · Molecular Therapy · doi:10.1038/mt.2010.85 · Cited by 1,261
From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus
Musunuru, K., Strong, A., Frank-Kamenetsky, M., Lee, N. E., Ahfeldt, T., Sachs, K. V., Li, X., Li, H., Kuperwasser, N., Ruda, V. M., et al. (2010) · Nature · doi:10.1038/nature09266 · Cited by 1,140
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Metadata
- Authors
- Frank-Kamenetsky, M., Grefhorst, A., Anderson, N. N., Racie, T. S., Bramlage, B., Akinc, A., Butler, D., Charisse, K., Dorkin, R., Fan, Y., Gamba-Vitalo, C., Hadwiger, P., Jayaraman, M., John, M., Jayaprakash, K. N., Maier, M., Nechev, L., Rajeev, K. G., Read, T., Röhl, I., Soutschek, J., Tan, P., Wong, J., Wang, G., Zimmermann, T., de Fougerolles, A., Vornlocher, H.-P., Langer, R., Anderson, D. G., Manoharan, M., Koteliansky, V., Horton, J. D., & Fitzgerald, K.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2008-08-19
- Volume
- 105
- Issue
- 33
- Pages
- 11915-11920
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2110083155
- Cited by
- 642
- References
- 6
- FWCI
- 46.55
- Type
- journal article
- Language
- en
- Open access
- green
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- Frank-Kamenetsky, M., Grefhorst, A., Anderson, N. N., Racie, T. S., Bramlage, B., Akinc, A., Butler, D., Charisse, K., Dorkin, R., Fan, Y., Gamba-Vitalo, C., Hadwiger, P., Jayaraman, M., John, M., Jayaprakash, K. N., Maier, M., Nechev, L., Rajeev, K. G., Read, T., . . . Fitzgerald, K. (2008). Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0805434105
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