Long-term stable reduction of low-density lipoprotein in nonhuman primates following in vivo genome editing of PCSK9

Wang, Lili; Breton, Camilo; Warzecha, Claude C.; Bell, Peter; Yan, Hanying; He, Zhenning; White, James R.; Zhu, Yanqing; Li, Mingyao; Buza, Elizabeth L.; Jantz, Derek; Wilson, James M.

doi:10.1016/j.ymthe.2021.02.020

Cited by 46 publications

(35 citation statements)

References 47 publications

(80 reference statements)

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“…The most recent set of studies have addressed a key step in the translation of therapeutic genome editing to human patients: demonstration of efficacy and safety in nonhuman primates. The first study used meganucleases rather than a CRISPR editor to target the PCSK9 gene ( 47 , 48 ). The investigators used an AAV vector encoding a meganuclease specific for a sequence in exon 7 of PCSK9 and expressed from a strong liver-specific promoter.…”

Section: Therapeutic Genome Editing: the Example Of Pcsk9mentioning

confidence: 99%

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Moving toward genome-editing therapies for cardiovascular diseases

Musunuru¹

2022

Journal of Clinical Investigation

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The rapid invention of genome-editing technologies over the past decade, which has already been transformative for biomedical research, has raised the tantalizing prospect of an entirely new therapeutic modality. Whereas the treatment of chronic cardiovascular diseases has heretofore entailed the use of chronic therapies that typically must be taken repeatedly and frequently for the remainder of the lifetime, genome editing will enable the development of “one-and-done” therapies with durable effects. This Review summarizes the variety of available genome-editing approaches, including nuclease editing, base editing, epigenome editing, and prime editing; illustrates how these various approaches could be implemented as novel therapies for cardiovascular diseases; and outlines a path from technology development to preclinical studies to clinical trials. Although this Review focuses on PCSK9 as an instructive example of the various genome-editing approaches under active investigation, the lessons learned will be broadly applicable to the treatment of a variety of diseases.

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Section: Therapeutic Genome Editing: the Example Of Pcsk9mentioning

confidence: 99%

“…(Lower AAV doses produced substantially lower editing rates.) The reductions persisted for at least 3 years ( 48 ).…”

Section: Therapeutic Genome Editing: the Example Of Pcsk9mentioning

confidence: 99%

Moving toward genome-editing therapies for cardiovascular diseases

Musunuru¹

2022

Journal of Clinical Investigation

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“…The injections were accompanied by transient elevations of serum transaminases due to a T cell response. The treated non-human primates were followed for up to three years and showed stable reductions in serum PCSK9 and LDL-C [41]. The initially detected off-target editing remained stable over time.…”

Section: Pcsk9 Editing Using a Meganucleasementioning

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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“…Indeed, were a sustained 65% reduction in LDL-C achievable in humans with CRISPR therapy, it would be expected to result in a substantial reduction in cardiovascular events in treated patients. A meganuclease-based therapy has also been investigated, although this achieved far lower levels of splice site editing and higher levels of off-target editing, including in human hepatocytes [63]. Whilst the demonstration of successful in vivo CRISPR targeting of PCSK9 in Cynomolgus monkeys represents the most advanced and promising approach to the use of CRISPR in the management of lipids and atherosclerosis, other approaches and targets are also of great interest as potential therapeutic strategies.…”

Section: Experimental Evidence Of Proof-of-conceptmentioning

confidence: 99%

CRISPR Gene Editing in Lipid Disorders and Atherosclerosis: Mechanisms and Opportunities

et al. 2021

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Elevated circulating concentrations of low-density lipoprotein cholesterol (LDL-C) have been conclusively demonstrated in epidemiological and intervention studies to be causally associated with the development of atherosclerotic cardiovascular disease. Enormous advances in LDL-C reduction have been achieved through the use of statins, and in recent years, through drugs targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of the hepatic LDL-receptor. Existing approaches to PCSK9 targeting have used monoclonal antibodies or RNA interference. Although these approaches do not require daily dosing, as statins do, repeated subcutaneous injections are nevertheless necessary to maintain effectiveness over time. Recent experimental studies suggest that clustered regularly interspaced short palindromic repeats (CRISPR) gene-editing targeted at PCSK9 may represent a promising tool to achieve the elusive goal of a ‘fire and forget’ lifelong approach to LDL-C reduction. This paper will provide an overview of CRISPR technology, with a particular focus on recent studies with relevance to its potential use in atherosclerotic cardiovascular disease.

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Long-term stable reduction of low-density lipoprotein in nonhuman primates following in vivo genome editing of PCSK9

Cited by 46 publications

References 47 publications

Moving toward genome-editing therapies for cardiovascular diseases

Moving toward genome-editing therapies for cardiovascular diseases

Gene Therapy Targeting PCSK9

CRISPR Gene Editing in Lipid Disorders and Atherosclerosis: Mechanisms and Opportunities

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