Gene Therapy Targeting PCSK9

Katzmann, Julius L.; Laufs, Ulrich

doi:10.3390/metabo12010070

Cited by 31 publications

(16 citation statements)

References 55 publications

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“…Additionally, assessment of the long-term tolerability, efficacy, and safety of inclisiran needs to be continued based on a larger group of patients ( Merćep et al, 2022 ). The gene therapy targeting PCSK9 has been reviewed recently by different research groups ( Henney et al, 2021 ; Miname et al, 2021 ; Katzmann et al, 2022 ).…”

Section: Therapies Targeting Ldl-pmentioning

confidence: 99%

Low-density lipoprotein particles in atherosclerosis

2022

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Among the diseases causing human death, cardiovascular disease (CVD) remains number one according to the World Health Organization report in 2021. It is known that atherosclerosis is the pathological basis of CVD. Low-density lipoprotein (LDL) plays a pivotal role in the initiation and progression of atherosclerotic CVD (ASCVD). LDL cholesterol (LDL-C) is the traditional biological marker of LDL. However, large numbers of patients who have achieved the recommended LDL-C goals still have ASCVD risk. In multiple prospective studies, LDL particle (LDL-P) is reported to be more accurate in predicting CVD risk than LDL-C. LDL-Ps differ in size, density and chemical composition. Numerous clinical studies have proved that the atherogenic mechanisms of LDL-Ps are determined not only by LDL number and size but also by LDL modifications. Of note, small dense LDL (sdLDL) particles possess stronger atherogenic ability compared with large and intermediate LDL subfractions. Besides, oxidized LDL (ox-LDL) is another risk factor in atherosclerosis. Among the traditional lipid-lowering drugs, statins induce dramatic reductions in LDL-C and LDL-P to a lesser extend. Recently, proprotein convertase subtilsin/kexin type 9 inhibitors (PCSK9i) have been demonstrated to be effective in lowering the levels of LDL-C, LDL-P, as well as CVD events. In this article, we will make a short review of LDL metabolism, discuss the discordance between LDL-C and LDL-P, outline the atherogenic mechanisms of action of LDL by focusing on sdLDL and ox-LDL, summarize the methods used for measurement of LDL subclasses, and conclude the advances in LDL-lowering therapies using statins and PCSK9i.

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Section: Therapies Targeting Ldl-pmentioning

confidence: 99%

Low-density lipoprotein particles in atherosclerosis

2022

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“…As a result, Musunuru et al upgraded their research, which is the most advanced PCSK9 in vivo editing attempt to date [ 51 ]. The employment of a specific base editor resulted in a very specific one-nucleotide exchange rather than double-strand breaks in the DNA, which is the most significant distinction from earlier studies [ 14 ]. Adenine base editing was found to be very effective in shutting down PCSK9 gene expression and function in the liver of a cynomolgus monkey in their trials, with over 60% editing achieved [ 51 ].…”

Section: Other Potential Model For Pcsk9 and Platelet Activation Rese...mentioning

confidence: 87%

“…Furthermore, those who had PCSK9 dysfunctional mutations also had reduced LDL-c levels and an 88% decreased risk of coronary artery disease [ 13 ]. Despite very low LDL-c blood levels, a family history of PCSK9 dysfunctional mutations does not correspond to negative health outcomes [ 14 ]. Therefore, PCSK9 has been identified as a possible target for the development of innovative cardiovascular disease therapeutics.…”

Section: Atherosclerosis Platelet Activation Myocardial Infarction (M...mentioning

confidence: 99%

“…NHPs were also reported to be an animal model for evaluating the genome editing-based technology, CRISPR/Cas9, in silencing the PCSK9 gene permanently. The principle of gene therapy in silencing PCSK9 utilizing CRISPR/Cas9 tools has been well-reviewed elsewhere [ 14 ]. Wang et al used this method in NHPs for the first time in vivo [ 49 , 50 ].…”

Section: Other Potential Model For Pcsk9 and Platelet Activation Rese...mentioning

confidence: 99%

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Recent Update on PCSK9 and Platelet Activation Experimental Research Methods: In Vitro and In Vivo Studies

Puteri

Azmi

Ridwan

et al. 2022

JCDD

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a crucial factor in the development and progression of cardiovascular diseases. PCSK9 has been demonstrated to modify LDL plasma levels and increase platelet activation, which promotes atherosclerosis, a defining feature of nearly all cardiovascular diseases. Platelet activation has been shown to promote and maintain the response to atherosclerosis development, from beginning to progression and exacerbation, which can lead to advanced cardiovascular events including myocardial infarction (MI) or death. Research on PCSK9 and platelet activation is currently underway with the main goal of reducing the risk of advanced cardiovascular events by preventing or slowing down atherosclerosis progression. Both in vitro and in vivo studies have been used to explore PCSK9 functions to develop new drugs targeting PCSK9. Finding the most suitable study models that represent the pathological and physiological systems found in humans is very important to achieving the goal. This review aimed to present a current and comprehensive overview of the experimental models that have been used to investigate the role of PCSK9 in platelet activation-induced atherosclerotic cardiovascular diseases.

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“…CRISPR gene editing has shown promising results, but problems with double-strand damage repair and off-target mutations persist. 75 Using the CRISPR or Cas system for genome editing has significant REVIEW advantages over previous methods. Designing and manufacturing RNAs (CRISPR/Cas systems) is inexpensive and straightforward.…”

Section: Acsvd: Effect Of Shear Stress On Ros Productionmentioning

confidence: 99%

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

et al. 2022

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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.

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Gene Therapy Targeting PCSK9

Cited by 31 publications

References 55 publications

Low-density lipoprotein particles in atherosclerosis

Low-density lipoprotein particles in atherosclerosis

Recent Update on PCSK9 and Platelet Activation Experimental Research Methods: In Vitro and In Vivo Studies

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

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