Reduced Blood Lipid Levels With In Vivo CRISPR-Cas9 Base Editing of ANGPTL3

Chadwick, Alexandra C.; Evitt, Niklaus H.; Lv, Wenjian; Musunuru, Kiran

doi:10.1161/circulationaha.117.031335

Cited by 136 publications

(98 citation statements)

References 6 publications

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“…Researchers produced adenoviral vectors containing a CRISPR-Cas9 base editor with a guide RNA targeting Gln-135 of ANGPTL3 and injected them into 5-week-old mice. 7 days after injection of the adenoviruses, plasma ANGPTL3 was reduced by 49%, plasma TG by 31%, and plasma cholesterol by 19% 80 . Deep sequencing of liver biopsies revealed no evidence of DNA edition at the top 10 most likely off-target sites.…”

Section: The Future: Crispr/crispr-associated 9 (Cas9)-based Investigmentioning

confidence: 96%

New Biotechnological Treatments for Lipid Disorders

Valencia-Enciso

Mendivil

2018

RIC

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Disorders of lipid and lipoprotein metabolism play a central role in the pathogenesis of atherosclerotic cardiovascular diseases (CVDs). Despite the widespread use of efficacious lipid-modifying therapies, the residual risk of CVD remains unacceptably high. The purpose of this manuscript is to review the application of new technologies in the treatment of lipid disorders. New therapies work mostly at the gene expression level and are, therefore, different from traditional small-molecule drugs that work mainly by inhibiting already synthesized proteins. We will briefly lay out the function of the gene products targeted by the new agents. Then, we will organize our review of new biotechnological treatments by the molecular approach, namely: monoclonal antibodies, antisense oligonucleotides, small-interfering RNAs, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated 9 (Cas9)-based genome editing. The paper concludes with the description of the current clinical studies and the perspectives for the use of these agents.

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Section: The Future: Crispr/crispr-associated 9 (Cas9)-based Investigmentioning

confidence: 96%

New Biotechnological Treatments for Lipid Disorders

Valencia-Enciso

Mendivil

2018

RIC

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“…Naturally occurring loss-of-function mutations in the angiopoietin-like 3 (ANGPTL3) gene are associated with reduced blood triglycerides and low-density lipoprotein cholesterol. Chadwick et al [126] obtained on average 35% on-target editing after intravenous injection of an Ad5 vector-bearing BE components targeting ANGPTL3 into mice. Another study performed by the same research group targeted the Pcsk9 gene using a similar in vivo method in mice [127].…”

Section: Single Nucleotide Mutations By Base Editorsmentioning

confidence: 99%

Adenovirus vectors in hematopoietic stem cell genome editing

Lieber

2019

FEBS Letters

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Genome editing of hematopoietic stem cells (HSCs) represents a therapeutic option for a number of hematological genetic diseases, as HSCs have the potential for self-renewal and differentiation into all blood cell lineages. This review presents advances of genome editing in HSCs utilizing adenovirus vectors as delivery vehicles. We focus on capsid-modified, helper-dependent adenovirus vectors that are devoid of all viral genes and therefore exhibit an improved safety profile. We discuss HSC genome engineering for several inherited disorders and infectious diseases including hemoglobinopathies, Fanconi anemia, hemophilia, and HIV-1 infection by ex vivo and in vivo editing in transgenic mice, nonhuman primates, as well as in human CD34 + cells. Mechanisms of therapeutic gene transfer including episomal expression of designer nucleases and base editors, transposase-mediated random integration, and targeted homology-directed repair triggered integration into selected genomic safe harbor loci are also reviewed.

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“…However, a recent study has shown that using CBEs to knockout the PCSK9 gene in the mouse liver leads to a substantial decrease in plasma PCSK9 protein levels (>50%), and cholesterol levels in plasma (about 30%), and causes no off‐target mutagenesis, neither cytosine‐to‐thymine edits nor indels (Chadwick, Wang, & Musunuru, ). Moreover, loss‐of‐function mutations in angiopoietin‐like 3 ( ANGPTL3 ), created by base editors, have provided a prospective strategy to treat patients with atherogenic dyslipidemia (Chadwick, Evitt, Lv, & Musunuru, ).…”

Section: Applications Of Crispr‐mediated Base Editingmentioning

confidence: 99%

Single‐nucleotide editing: From principle, optimization to application

2019

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Cytosine base editors (CBEs) and adenine base editors (ABEs), which are generally composed of an engineered deaminase and a catalytically impaired CRISPR-Cas9 variant, are new favorite tools for single base substitution in cells and organisms. In this review, we summarize the principle of base-editing systems and elaborate on the evolution of different platforms of CBEs and ABEs, including their deaminase, Cas9 variants, and editing outcomes. Moreover, we highlight their applications in mouse and human cells and discuss the challenges and prospects of base editors. The ABEand CBE systems have been used in gene silencing, pathogenic gene correction, and functional genetic screening. Single base editing is becoming a new promising genetic tool in biomedical research and gene therapy.

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Reduced Blood Lipid Levels With In Vivo CRISPR-Cas9 Base Editing of ANGPTL3

Cited by 136 publications

References 6 publications

New Biotechnological Treatments for Lipid Disorders

New Biotechnological Treatments for Lipid Disorders

Adenovirus vectors in hematopoietic stem cell genome editing

Single‐nucleotide editing: From principle, optimization to application

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