Abstract
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.
Highlights
Genome editing holds the potential to revolutionize the treatment of chronic cardiovascular diseases, such as coronary heart disease
Besides outlining the varied genome-editing approaches that are available for use, this Review focuses on the gene for which, by far, the most proof-of-concept studies have been reported — proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of blood cholesterol levels and driver of coronary heart disease risk — with the goal of illustrating for the reader the various ways in which the field is advancing the development of genome-editing therapies for cardiovascular diseases
There was about 50% non-homologous end joining (NHEJ)-mediated editing of the human PCSK9 alleles present in the humanized liver, with no editing observed at a handful of candidate off-target sites, along with about 50% reduction of human PCSK9 protein levels in the blood
Summary
REVIEW SERIES: NEW THERAPEUTIC TARGETS IN CARDIOVASCULAR DISEASES Series Editor: Daniel P. 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. 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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