CRISPR-Cas9 Targeting PCSK9: A Promising Therapeutic Approach for Atherosclerosis

World Health Organization. Cardiovascular diseases (cvds). Available at: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds), 2021 accessed January 22, 2023

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22. https://doi.org/10.1056/NEJMoa1615664.

Article  CAS  PubMed  Google Scholar 

Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated ldl cholesterol. N Engl J Med. 2020;382(16):1507–19. https://doi.org/10.1056/NEJMoa1912387.

Article  CAS  PubMed  Google Scholar 

Doudna JA, Charpentier E. The new frontier of genome engineering with crispr-cas9. Science. 2014;346(6213):1258096. https://doi.org/10.1126/science.1258096.

Article  CAS  PubMed  Google Scholar 

Pickar-Oliver A, Gersbach CA. The next generation of crispr-cas technologies and applications. Nat Rev Mol Cell Biol. 2019;20(8):490–507. https://doi.org/10.1038/s41580-019-0131-5.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lagace TA. Pcsk9 and ldlr degradation: regulatory mechanisms in circulation and in cells. Curr Opin Lipidol. 2014;25(5):387–93. https://doi.org/10.1097/MOL.0000000000000114.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cohen JC, Boerwinkle E, Mosley TH, et al. Sequence variations in pcsk9, low ldl, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264–72. https://doi.org/10.1056/NEJMoa054013.

Article  CAS  PubMed  Google Scholar 

Leren TP. Mutations in the pcsk9 gene in norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet. 2004;65(5):419–22. https://doi.org/10.1111/j.0009-9163.2004.0238.x.

Article  CAS  PubMed  Google Scholar 

Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–107. https://doi.org/10.1056/NEJMoa1801174.

Article  CAS  PubMed  Google Scholar 

Musunuru K, Chadwick AC, Mizoguchi T, et al. In vivo crispr base editing of pcsk9 durably lowers cholesterol in primates. Nature. 2021;593(7859):429–34. https://doi.org/10.1038/s41586-021-03534-y.

Article  CAS  PubMed  Google Scholar 

Ding Q, Strong A, Patel KM, et al. Permanent alteration of pcsk9 with in vivo crispr-cas9 genome editing. Circ Res. 2014;115(5):488–92. https://doi.org/10.1161/CIRCRESAHA.115.304351.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rothgangl T, Dennis MK, Lin PJ, et al. In vivo adenine base editing of pcsk9 in macaques reduces ldl cholesterol levels. Nat Biotechnol. 2021;39(8):949–57. https://doi.org/10.1038/s41587-021-00933-4.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Musunuru K. Crispr and cardiovascular diseases. Cardiovasc Res. 2023;119(1):79–93. https://doi.org/10.1093/cvr/cvac048.

Article  CAS  PubMed  Google Scholar 

Rashid S, Tavori H, Brown PE, et al. Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein b lipoproteins through both low-density lipoprotein receptor-dependent and-independent mechanisms. Circulation. 2014;130(5):431–41. https://doi.org/10.1161/CIRCULATIONAHA.113.006720.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tavori H, Fan D, Blakemore JL, et al. Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation. Circulation. 2013;127(24):2403–13. https://doi.org/10.1161/CIRCULATIONAHA.113.001592.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lakoski SG, Lagace TA, Cohen JC, et al. Genetic and metabolic determinants of plasma pcsk9 levels. The Journal of Clinical Endocrinology & Metabolism. 2009;94(7):2537–43. https://doi.org/10.1210/jc.2009-0141.

Article  CAS  Google Scholar 

Cariou B, Le May C, Costet P. Clinical aspects of pcsk9. Atherosclerosis. 2011;216(2):258–65. https://doi.org/10.1016/j.atherosclerosis.2011.04.018.

Article  CAS  PubMed  Google Scholar 

Raal FJ, Giugliano RP, Sabatine MS, et al. Pcsk9 inhibition-mediated reduction in lp(a) with evolocumab: an analysis of 10 clinical trials and the ldl receptor’s role. J Lipid Res. 2016;57(6):1086–96. https://doi.org/10.1194/jlr.P065334.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tavori H, Christian D, Minnier J, et al. Pcsk9 association with lipoprotein (a). Circ Res. 2016;119(1):29–35. https://doi.org/10.1161/CIRCRESAHA.116.308811.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cheng JM, Oemrawsingh RM, Garcia-Garcia HM, et al. Pcsk9 in relation to coronary plaque inflammation: Results of the atheroremo-ivus study. Atherosclerosis. 2016;248:117–22. https://doi.org/10.1016/j.atherosclerosis.2016.03.010.

Article  CAS  PubMed  Google Scholar 

Denis M, Marcinkiewicz J, Zaid A, et al. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation. 2012;125(7):894–901. https://doi.org/10.1161/CIRCULATIONAHA.111.057406.

Article  CAS  PubMed  Google Scholar 

Katsuki S, Jha PK, Lupieri A, et al. Proprotein convertase subtilisin/kexin 9 (pcsk9) promotes macrophage activation via ldl receptor-independent mechanisms. Circ Res. 2022;131(11):873–89. https://doi.org/10.1161/CIRCRESAHA.121.320056.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ricci C, Ruscica M, Camera M, et al. Pcsk9 induces a pro-inflammatory response in macrophages. Sci Rep. 2018;8(1):1–10. https://doi.org/10.1038/s41598-018-20425-x.

Article  CAS  Google Scholar 

Kuhnast S, van der Hoorn JW, Pieterman EJ, et al. Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin. J Lipid Res. 2014;55(10):2103–12. https://doi.org/10.1194/jlr.M051326.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ding Z, Liu S, Wang X, et al. Hemodynamic shear stress via ros modulates pcsk9 expression in human vascular endothelial and smooth muscle cells and along the mouse aorta. Antioxid Redox Signal. 2015;22(9):760–71. https://doi.org/10.1089/ars.2014.6054.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang Y, et al. Interactions between pcsk9 and nlrp3 inflammasome signaling in atherosclerosis. Front Immunol. 2023;14:1126823. https://doi.org/10.3389/fimmu.2023.1126823.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Huang L, Li Y, Cheng Z, et al. Pcsk9 promotes endothelial dysfunction during sepsis via the tlr4/myd88/nf-\(\kappa \)b and nlrp3 pathways. Inflammation. 2023;46(1):115–28. https://doi.org/10.1007/s10753-022-01715-z.

Article  CAS  PubMed  Google Scholar 

Navarese EP, Kolodziejczak M, Winter MP, et al. Association of pcsk9 with platelet reactivity in patients with acute coronary syndrome treated with prasugrel or ticagrelor: the pcsk9-react study. Int J Cardiol. 2015;227:644–9. https://doi.org/10.1016/j.ijcard.2016.10.084.

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