CRISPR-Cas9 Genome Editing for Treatment of Atherogenic Dyslipidemia

Chadwick, Alexandra C.; Musunuru, Kiran

doi:10.1161/atvbaha.117.309326

Cited by 21 publications

(8 citation statements)

References 70 publications

(55 reference statements)

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“…Recent discovery of CRISPR-Cas has revolutionized genome editing techniques, shedding light on future cardiovascular gene therapies. For instance, viral delivery of CRISPR-Cas has been used to treat atherosclerosis in mice by targeting lipogenic genes in the liver ( 52 , 53 ). Leveraging on the efficient CRISPR-Cas–based gene deletion and capitalizing on the critical role of endothelial TXNDC5 in DF-induced atherosclerosis, we devised a new approach integrating nanocarriers and CDH5 -driven CRISPR-Cas9 plasmids to specifically delete Txndc5 in vascular endothelium, resulting in increased eNOS protein and reduced atherosclerosis in ApoE −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo

et al. 2022

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Although atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed flow (DF) activates endothelium, therapies targeting flow-dependent mechanosensing pathways in the vasculature are unavailable. Here, we provided experimental evidence demonstrating a previously unidentified causal role of DF-induced endothelial TXNDC5 (thioredoxin domain containing 5) in atherosclerosis. TXNDC5 was increased in human and mouse atherosclerotic lesions and induced in endothelium subjected to DF. Endothelium-specific Txndc5 deletion markedly reduced atherosclerosis in ApoE −/− mice. Mechanistically, DF-induced TXNDC5 increases proteasome-mediated degradation of heat shock factor 1, leading to reduced heat shock protein 90 and accelerated eNOS (endothelial nitric oxide synthase) protein degradation. Moreover, nanoparticles formulated to deliver Txndc5 -targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter ( CDH5 ) significantly increase eNOS protein and reduce atherosclerosis in ApoE −/− mice. These results delineate a new molecular paradigm that DF-induced endothelial TXNDC5 promotes atherosclerosis and establish a proof of concept of targeting endothelial mechanosensitive pathways in vivo against atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo

et al. 2022

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“…Strategies to overcome this limitation include the use of different Cas9 proteins and mutagenesis of the protein which influences its PAM specificity [35]. Moreover, to date, gene editing has to be considered an irrevocable treatment which, in case of adverse effects, cannot be discontinued as conventional drugs can [36]. Finally, current methods in genome editing are highly variable in their efficiency, depending on the genetic locus and the tissue.…”

Section: Advantages and Limitations Of Crispr/cas Genome Editingmentioning

confidence: 99%

Gene Therapy Targeting PCSK9

Katzmann

Laufs

2022

Metabolites

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The last decades of research in cardiovascular prevention have been characterized by successful bench-to-bedside developments for the treatment of low-density lipoprotein (LDL) hypercholesterolemia. Recent examples include the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) with monoclonal antibodies, small interfering RNA and antisense RNA drugs. The cumulative effects of LDL cholesterol on atherosclerosis make early, potent, and long-term reductions in LDL cholesterol desirable—ideally without the need of regular intake or application of medication and importantly, without side effects. Current reports show durable LDL cholesterol reductions in primates following one single treatment with PCSK9 gene or base editors. Use of the CRISPR/Cas system enables precise genome editing down to single-nucleotide changes. Provided safety and documentation of a reduction in cardiovascular events, this novel technique has the potential to fundamentally change our current concepts of cardiovascular prevention. In this review, the application of the CRISPR/Cas system is explained and the current state of in vivo approaches of PCSK9 editing is presented.

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“…The fact that PCG1α is decreased in the VSMC of atherosclerotic vessels highlights the role of the PCG1α/NRF1/miR-378a axis in atheroprotection [ 44 ]. Moreover, a new technique in genetic and epigenetic studies has appeared in recent years—gene editing, a procedure in which certain fragments of genes or non-coding sequences can be altered with the use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) systems built up with guide RNA [ 45 , 46 ]. This method opens up new horizons in the area of precise genomic and epigenomic research.…”

Section: Exploration Of Epigenetic Regulations and Genetic Patternmentioning

confidence: 99%

Pathophysiology of Atherosclerotic Plaque Development-Contemporary Experience and New Directions in Research

Kowara

Cudnoch‐Jędrzejewska

2021

IJMS

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Atherosclerotic plaque is the pathophysiological basis of important and life-threatening diseases such as myocardial infarction. Although key aspects of the process of atherosclerotic plaque development and progression such as local inflammation, LDL oxidation, macrophage activation, and necrotic core formation have already been discovered, many molecular mechanisms affecting this process are still to be revealed. This minireview aims to describe the current directions in research on atherogenesis and to summarize selected studies published in recent years—in particular, studies on novel cellular pathways, epigenetic regulations, the influence of hemodynamic parameters, as well as tissue and microorganism (microbiome) influence on atherosclerotic plaque development. Finally, some new and interesting ideas are proposed (immune cellular heterogeneity, non-coding RNAs, and immunometabolism) which will hopefully bring new discoveries in this area of investigation.

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CRISPR-Cas9 Genome Editing for Treatment of Atherogenic Dyslipidemia

Cited by 21 publications

References 70 publications

Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo

Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo

Gene Therapy Targeting PCSK9

Pathophysiology of Atherosclerotic Plaque Development-Contemporary Experience and New Directions in Research

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