Skip to main content Skip to main navigation menu Skip to site footer

A review of CRISPR Cas9 for ASCVD: treatment strategies and could target PSCK9 gene using CRISPR cas9 prevent the patient from atherosclerotic vascular disease?


Background: Targeting PCSK9 by maintaining hemodynamic shear stress stability has been shown in several studies to reduce LDL-C, arterial plaque formation, and PCSK9 expression in atherosclerotic cardiovascular disease. Genome editing with CRISPR-associated regularly interspersed short palindromic repeats (CRISPR/Cas9) have therapeutic potential for atherosclerotic cardiovascular disease. This study aims to evaluate the role of CRISPR/Cas9 in targeting PCSK9 as an effective therapeutic and long-term effect on atherosclerotic vascular disease.

Methods: The method used in this study summarizes the article by looking for keywords that have been determined in the title and abstract. The authors used official guidelines from Science Direct, PubMed, the American College of Cardiology, Google Scholar, and PERKI to select full-text articles published within the last decade, prioritizing searches within the last five years.

Results: CRISPR/Cas9 deletion of PCSK9 in mouse models reduces LDL-C, Plaque accumulation in the arteries, and PCSK9 expression. Furthermore, CRISPR/Cas9 deletion in PCSK9 saves the stability of Hemodyanimc shear stress to control the PCSK9 expression that causes Atherosclerotic cardiovascular disease.

Conclusion: PCSK9 targeting by CRISPR/Cas9 deletion effectively reduces LDL-C, plaque buildup in the arteries, and PCSK9 expression. However, more research is needed to determine its side effects and safety.


  1. Paul S, Lancaster GI, Meikle PJ. Plasmalogens: A potential therapeutic target for neurodegenerative and cardiometabolic disease. Prog Lipid Res. 2019;74:186-195.
  2. Mohd Nor NS, Al-Khateeb AM, Chua YA, Mohd Kasim NA, Mohd Nawawi H. Heterozygous familial hypercholesterolaemia in a pair of identical twins: a case report and updated review. BMC Pediatr. 2019;19(1):106.
  3. Dichgans M, Pulit SL, Rosand J. Stroke genetics: discovery, biology, and clinical applications. Lancet Neurol. 2019;18(6):587-599.
  4. Doodnauth SA, Grinstein S, Maxson ME. Constitutive and stimulated macropinocytosis in macrophages: roles in immunity and in the pathogenesis of atherosclerosis. Philos Trans R Soc Lond B Biol Sci. 2019;374(1765):20180147.
  5. Reiss AB, Grossfeld D, Kasselman LJ, Renna HA, Vernice NA, Drewes W, et al. Adenosine and the Cardiovascular System. Am J Cardiovasc Drugs. 2019;19(5):449-464.
  6. Shafi S, Ansari HR, Bahitham W, Aouabdi S. The Impact of Natural Antioxidants on the Regenerative Potential of Vascular Cells. Front Cardiovasc Med. 2019;6:28.
  7. GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1151-1210.
  8. Maharani A, Sujarwoto, Praveen D, Oceandy D, Tampubolon G, Patel A. Cardiovascular disease risk factor prevalence and estimated 10-year cardiovascular risk scores in Indonesia: The SMARThealth Extend study. PLoS One. 2019;14(4):e0215219.
  9. Kiaie N, Gorabi AM, Penson PE, Watts G, Johnston TP, Banach M, et al. A new approach to the diagnosis and treatment of atherosclerosis: the era of the liposome. Drug Discov Today. 2020;25(1):58-72.
  10. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472.
  11. Prabawa IPY, Lestari AAW, Muliarta IM, Mardhika PE, Pertiwi GAR, Bhargah A, et al. The Stromal Cell-derived Factor-1/CXCL12 3'A-gene Polymorphism is Related to the Increased Risk of Coronary Artery Disease: A Systematic Review and Meta-analysis. Open Access Macedonian Journal of Medical Sciences. 2020;8(F):197-202.
  12. Nayor M, Brown KJ, Vasan RS. The Molecular Basis of Predicting Atherosclerotic Cardiovascular Disease Risk. Circ Res. 2021;128(2):287-303.
  13. Gallego-Colon E, Daum A, Yosefy C. Statins and PCSK9 inhibitors: A new lipid-lowering therapy. Eur J Pharmacol. 2020;878:173114.
  14. Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, et al. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018;98(6):1141-1154.e7.
  15. Ismawati, Romus I, Mukhyarjon, Salsabilqis J, Wulandari N. Effect of proteasome inhibitor on serum 8-OHdG and aortic SOD2 in a rat model of atherosclerosis. Bali Medical Journal. 2022;11(1):391-396.
  16. Ohta H, Liu X, Maeda M. Autologous adipose mesenchymal stem cell administration in arteriosclerosis and potential for anti-aging application: a retrospective cohort study. Stem Cell Res Ther. 2020;11(1):538.
  17. Soliman GA. Dietary Fiber, Atherosclerosis, and Cardiovascular Disease. Nutrients. 2019;11(5):1155.
  18. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020;141(9):e139-e596.
  19. Libby P. The changing landscape of atherosclerosis. Nature. 2021;592(7855):524-533.
  20. Bergheanu SC, Bodde MC, Jukema JW. Pathophysiology and treatment of atherosclerosis : Current view and future perspective on lipoprotein modification treatment. Neth Heart J. 2017;25(4):231-242.
  21. Xu S, Xu Y, Yin M, Zhang S, Liu P, Koroleva M, Si S, Little PJ, Pelisek J, Jin ZG. Flow-dependent epigenetic regulation of IGFBP5 expression by H3K27me3 contributes to endothelial anti-inflammatory effects. Theranostics. 2018;8(11):3007-3021.
  22. Sascău R, Clement A, Radu R, Prisacariu C, Stătescu C. Triglyceride-Rich Lipoproteins and Their Remnants as Silent Promoters of Atherosclerotic Cardiovascular Disease and Other Metabolic Disorders: A Review. Nutrients. 2021;13(6):1774.
  23. Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG, Kuivenhoven JA, Averna M, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2(8):655-666.
  24. Bai Y, Huang R, Wan L, Zhao R. Association between CYP2C19 gene polymorphisms and lipid metabolism in Chinese patients with ischemic stroke. J Int Med Res. 2020;48(7):300060520934657.
  25. Cao G, Xuan X, Zhang R, Hu J, Dong H. Gene Therapy for Cardiovascular Disease: Basic Research and Clinical Prospects. Front Cardiovasc Med. 2021;8:760140.
  26. Wang H, La Russa M, Qi LS. CRISPR/Cas9 in Genome Editing and Beyond. Annu Rev Biochem. 2016;85:227-264.
  27. Gasiunas G, Barrangou R, Horvath P, Siksnys V. Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proc Natl Acad Sci U S A. 2012;109(39):E2579-E2586.
  28. Ding Q, Strong A, Patel KM, Ng SL, Gosis BS, Regan SN, et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res. 2014;115(5):488-92.
  29. Ran FA, Cong L, Yan WX, Scott DA, Gootenberg JS, Kriz AJ, et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature. 2015;520(7546):186-91.
  30. Wang X, Raghavan A, Chen T, Qiao L, Zhang Y, Ding Q, Musunuru K. CRISPR-Cas9 Targeting of PCSK9 in Human Hepatocytes In Vivo-Brief Report. Arterioscler Thromb Vasc Biol. 2016;36(5):783-6.
  31. Musunuru K, Chadwick AC, Mizoguchi T, Garcia SP, DeNizio JE, Reiss CW, et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature. 2021;593(7859):429-434.
  32. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816-821.
  33. Chadwick AC, Musunuru K. Treatment of Dyslipidemia Using CRISPR/Cas9 Genome Editing. Curr Atheroscler Rep. 2017;19(7):32.
  34. Porto EM, Komor AC, Slaymaker IM, Yeo GW. Base editing: advances and therapeutic opportunities. Nat Rev Drug Discov. 2020;19(12):839-859.
  35. Bayat H, Omidi M, Rajabibazl M, Sabri S, Rahimpour A. The CRISPR Growth Spurt: from Bench to Clinic on Versatile Small RNAs. J Microbiol Biotechnol. 2017;27(2):207-218.
  36. Jiang C, Mei M, Li B, Zhu X, Zu W, Tian Y, et al. A non-viral CRISPR/Cas9 delivery system for therapeutically targeting HBV DNA and pcsk9 in vivo. Cell Res. 2017;27(3):440-443.
  37. Jarrett KE, Lee C, De Giorgi M, Hurley A, Gillard BK, Doerfler AM, Li A, Pownall HJ, Bao G, Lagor WR. Somatic Editing of Ldlr With Adeno-Associated Viral-CRISPR Is an Efficient Tool for Atherosclerosis Research. Arterioscler Thromb Vasc Biol. 2018;38(9):1997-2006. d
  38. Tessadori F, Roessler HI, Savelberg SMC, Chocron S, Kamel SM, Duran KJ, van Haelst MM, van Haaften G, Bakkers J. Effective CRISPR/Cas9-based nucleotide editing in zebrafish to model human genetic cardiovascular disorders. Dis Model Mech. 2018;11(10):dmm035469.
  39. Long C, McAnally JR, Shelton JM, Mireault AA, Bassel-Duby R, Olson EN. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science. 2014;345(6201):1184-1188.
  40. Yang S, Chang R, Yang H, Zhao T, Hong Y, Kong HE, et al. CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease. J Clin Invest. 2017;127(7):2719-2724.
  41. Rohn TT, Kim N, Isho NF, Mack JM. The Potential of CRISPR/Cas9 Gene Editing as a Treatment Strategy for Alzheimer's Disease. J Alzheimers Dis Parkinsonism. 2018;8(3):439.
  42. Li T, Pires C, Nielsen TT, Waldemar G, Hjermind LE, Nielsen JE, et al. Generation of induced pluripotent stem cells (iPSCs) from an Alzheimer's disease patient carrying an A79V mutation in PSEN1. Stem Cell Res. 2016;16(2):229-32.
  43. Sharma G, Sharma AR, Bhattacharya M, Lee SS, Chakraborty C. CRISPR-Cas9: A Preclinical and Clinical Perspective for the Treatment of Human Diseases. Mol Ther. 2021;29(2):571-586.
  44. Osborn MJ, Gabriel R, Webber BR, DeFeo AP, McElroy AN, Jarjour J, et al. Fanconi anemia gene editing by the CRISPR/Cas9 system. Hum Gene Ther. 2015;26(2):114-26.
  45. Shao Y, Wang L, Guo N, Wang S, Yang L, Li Y, et al. Cas9-nickase-mediated genome editing corrects hereditary tyrosinemia in rats. J Biol Chem. 2018;293(18):6883-6892.
  46. Wen J, Tao W, Hao S, Zu Y. Cellular function reinstitution of offspring red blood cells cloned from the sickle cell disease patient blood post CRISPR genome editing. J Hematol Oncol. 2017;10(1):119.
  47. Xie F, Ye L, Chang JC, Beyer AI, Wang J, Muench MO, et al. Seamless gene correction of β-thalassemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyBac. Genome Res. 2014;24(9):1526-33.
  48. Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell. 2013;13(6):653-658.
  49. Bakondi B, Lv W, Lu B, Jones MK, Tsai Y, Kim KJ, et al. In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa. Mol Ther. 2016 Mar;24(3):556-63.
  50. Wang X, Raghavan A, Chen T, Qiao L, Zhang Y, Ding Q, et al. CRISPR-Cas9 Targeting of PCSK9 in Human Hepatocytes In Vivo-Brief Report. Arterioscler Thromb Vasc Biol. 2016;36(5):783-6.
  51. Ebina H, Misawa N, Kanemura Y, Koyanagi Y. Harnessing the CRISPR/Cas9 system to disrupt latent HIV-1 provirus. Sci Rep. 2013;3:2510.
  52. Dong C, Qu L, Wang H, Wei L, Dong Y, Xiong S. Targeting hepatitis B virus cccDNA by CRISPR/Cas9 nuclease efficiently inhibits viral replication. Antiviral Res. 2015;118:110-117.
  53. Chen J, Sathiyamoorthy K, Zhang X, Schaller S, Perez White BE, Jardetzky TS, et al. Ephrin receptor A2 is a functional entry receptor for Epstein-Barr virus. Nat Microbiol. 2018;3(2):172-180.
  54. Valletta S, Dolatshad H, Bartenstein M, Yip BH, Bello E, Gordon S, et al. ASXL1 mutation correction by CRISPR/Cas9 restores gene function in leukemia cells and increases survival in mouse xenografts. Oncotarget. 2015;6(42):44061-71.
  55. Aubrey BJ, Kelly GL, Kueh AJ, Brennan MS, O'Connor L, Milla L, et al. An inducible lentiviral guide RNA platform enables the identification of tumor-essential genes and tumor-promoting mutations in vivo. Cell Rep. 2015;10(8):1422-32.
  56. Feng Y, Sassi S, Shen JK, Yang X, Gao Y, Osaka E, et al. Targeting CDK11 in osteosarcoma cells using the CRISPR-Cas9 system. J Orthop Res. 2015;33(2):199-207.
  57. Feng W, Li HC, Xu K, Chen YF, Pan LY, Mei Y, et al. SHCBP1 is over-expressed in breast cancer and is important in the proliferation and apoptosis of the human malignant breast cancer cell line. Gene. 2016;587(1):91-97.
  58. Lian YF, Yuan J, Cui Q, Feng QS, Xu M, Bei JX, et al. Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma. PLoS One. 2016;11(3):e0152820.
  59. Tang H, Shrager JB. CRISPR/Cas-mediated genome editing to treat EGFR-mutant lung cancer: a personalized molecular surgical therapy. EMBO Mol Med. 2016;8(2):83-85.
  60. Chu HW, Rios C, Huang C, Wesolowska-Andersen A, Burchard EG, O'Connor BP, et al. CRISPR-Cas9-mediated gene knockout in primary human airway epithelial cells reveals a pro-inflammatory role for MUC18. Gene Ther. 2015;22(10):822-829.
  61. Malaviya R, Laskin DL, Malaviya R. Janus kinase-3 dependent inflammatory responses in allergic asthma. Int Immunopharmacol. 2010;10(8):829-836.
  62. Ding Z, Liu S, Wang X, Deng X, Fan Y, Sun C, 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.
  63. Cominacini L, Pasini AF, Garbin U, Davoli A, Tosetti ML, Campagnola M, et al. Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappaB through an increased production of intracellular reactive oxygen species. J Biol Chem. 2000 Apr 28;275(17):12633-8.
  64. Conway DE, Breckenridge MT, Hinde E, Gratton E, Chen CS, Schwartz MA. Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1. Curr Biol. 2013;23(11):1024-1030.
  65. Wang J, Wang Y, Sheng L, He T, Nin X, Xue A, et al. High fluid shear stress prevents atherosclerotic plaque formation by promoting endothelium denudation and synthetic phenotype of vascular smooth muscle cells. Mol Med Rep. 2021;24(2):577.
  66. Chiu JJ, Wung BS, Shyy JY, Hsieh HJ, Wang DL. Reactive oxygen species are involved in shear stress-induced intercellular adhesion molecule-1 expression in endothelial cells. Arterioscler Thromb Vasc Biol. 1997;17(12):3570-3577.
  67. Brandes RP, Kreuzer J. Vascular NADPH oxidases: molecular mechanisms of activation. Cardiovasc Res. 2005;65(1):16-27.
  68. Raaz U, Toh R, Maegdefessel L, Adam M, Nakagami F, Emrich FC, et al. Hemodynamic regulation of reactive oxygen species: implications for vascular diseases. Antioxid Redox Signal. 2014;20(6):914-28.
  69. Siew WS, Tang YQ, Kong CK, Goh BH, Zacchigna S, Dua K, et al. Harnessing the Potential of CRISPR/Cas in Atherosclerosis: Disease Modeling and Therapeutic Applications. Int J Mol Sci. 2021;22(16):8422.
  70. Chadwick AC, Musunuru K. CRISPR-Cas9 Genome Editing for Treatment of Atherogenic Dyslipidemia. Arterioscler Thromb Vasc Biol. 2018;38(1):12-18.
  71. Zheng T, Hou Y, Zhang P, Zhang Z, Xu Y, Zhang L, et al. Profiling single-guide RNA specificity reveals a mismatch sensitive core sequence. Sci Rep. 2017;7:40638.
  72. Tsai SQ, Joung JK. Defining and improving the genome-wide specificities of CRISPR-Cas9 nucleases. Nat Rev Genet. 2016;17(5):300-312.
  73. Lino CA, Harper JC, Carney JP, Timlin JA. Delivering CRISPR: a review of the challenges and approaches. Drug Deliv. 2018;25(1):1234-1257.
  74. Dai WJ, Zhu LY, Yan ZY, Xu Y, Wang QL, Lu XJ. CRISPR-Cas9 for in vivo Gene Therapy: Promise and Hurdles. Mol Ther Nucleic Acids. 2016;5(8):e349.
  75. Katzmann JL, Cupido AJ, Laufs U. Gene Therapy Targeting PCSK9. Metabolites. 2022;12(1):70.
  76. Xu J, Shapiro MD. Current evidence and future directions of PCSK9 inhibition. US Cardiology Review. 2021;15(1):1-7.
  77. Janik E, Niemcewicz M, Ceremuga M, Krzowski L, Saluk-Bijak J, Bijak M. Various Aspects of a Gene Editing System-CRISPR-Cas9. Int J Mol Sci. 2020;21(24):9604.
  78. Prabawa IPY, Lestari AAW, Muliarta IM, Mardhika PE, Pertiwi GAR, Bhargah A, et al. The Stromal Cell-derived Factor-1/CXCL12 3'A-gene Polymorphism is Related to the Increased Risk of Coronary Artery Disease: A Systematic Review and Meta-analysis. Open Access Macedonian Journal of Medical Sciences. 2020;8(F):197-202.

How to Cite

Suwito, B. E., Adji, A. S., Wardani, V. A. K., Widjaja, J. S., Angel, S. C. S., & Rahman, F. S. (2022). A review of CRISPR Cas9 for ASCVD: treatment strategies and could target PSCK9 gene using CRISPR cas9 prevent the patient from atherosclerotic vascular disease?. Bali Medical Journal, 11(2), 985–993.




Search Panel

Bambang Edi Suwito
Google Scholar
BMJ Journal

Arga Setyo Adji
Google Scholar
BMJ Journal

Vira Aulia Kusuma Wardani
Google Scholar
BMJ Journal

Jordan Steven Widjaja
Google Scholar
BMJ Journal

Syalomitha Claudia Stefanie Angel
Google Scholar
BMJ Journal

Firman Suryadi Rahman
Google Scholar
BMJ Journal