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Perspective
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The NIH Somatic Cell Genome Editing program
This Perspective discusses how the Somatic Cell Genome Editing Consortium aims to accelerate the implementation of safe and effective genome-editing therapies in the clinic.
- Krishanu Saha
- , Erik J. Sontheimer
- & Jiangbing Zhou
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Article |
In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice
In a mouse model of progeria, an adenine base editor delivered with adeno-associated virus corrects the pathogenic mutation in LMNA, rescues vascular pathology and markedly extends the lifespan of the mice.
- Luke W. Koblan
- , Michael R. Erdos
- & David R. Liu
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Article |
Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA
Genomic integration of an adeno-associated virus vector in a mouse model of Angelman syndrome unsilences paternal Ube3a and rescues anatomical and behavioural phenotypes, suggesting a pathway towards the treatment of this neurodevelopmental disorder.
- Justin M. Wolter
- , Hanqian Mao
- & Mark J. Zylka
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A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing
An interbacterial toxin that catalyses the deamination of cytidines within double-stranded DNA forms part of a CRISPR-free, RNA-free base editing system that enables manipulation of human mitochondrial DNA.
- Beverly Y. Mok
- , Marcos H. de Moraes
- & David R. Liu
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Article |
Search-and-replace genome editing without double-strand breaks or donor DNA
A new DNA-editing technique called prime editing offers improved versatility and efficiency with reduced byproducts compared with existing techniques, and shows potential for correcting disease-associated mutations.
- Andrew V. Anzalone
- , Peyton B. Randolph
- & David R. Liu
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Letter |
Precise therapeutic gene correction by a simple nuclease-induced double-stranded break
Disease-causing microduplications can be corrected by harnessing an endogenous double-stranded break DNA repair pathway.
- Sukanya Iyer
- , Sneha Suresh
- & Scot A. Wolfe
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CasX enzymes comprise a distinct family of RNA-guided genome editors
CRISPR–CasX represents a distinct RNA-guided platform that is functionally separate from Cas9 and Cas12a and is active for bacterial and human genome modification.
- Jun-Jie Liu
- , Natalia Orlova
- & Jennifer A. Doudna
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Letter |
Reprogramming human T cell function and specificity with non-viral genome targeting
A non-viral strategy to introduce large DNA sequences into T cells enables the correction of a pathogenic mutation that causes autoimmunity, and the replacement of an endogenous T-cell receptor with an engineered receptor that can recognize cancer antigens.
- Theodore L. Roth
- , Cristina Puig-Saus
- & Alexander Marson
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Article |
Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage
A new DNA ‘base editor’ can change targeted A•T base pairs to G•C, allowing disease-associated mutations to be corrected and disease-suppressing mutations to be introduced into cells.
- Nicole M. Gaudelli
- , Alexis C. Komor
- & David R. Liu
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Letter |
Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection
Introducing chimeric antigen receptors into the endogenous T-cell receptor locus reduces tonic signalling, averts accelerated T-cell differentiation and delays T-cell exhaustion, leading to enhanced function and anti-tumour efficacy compared to random integrations.
- Justin Eyquem
- , Jorge Mansilla-Soto
- & Michel Sadelain
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Letter |
Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage
CRISPR/Cas9 DNA editing creates a double-stranded break in the target DNA, which can frequently generate random insertion or deletion of bases (indels); a new genome editing approach combining Cas9 with a cytidine deaminase is described here, which corrects point mutations more efficiently than canonical Cas9, while avoiding double-stranded breaks and indel formation.
- Alexis C. Komor
- , Yongjoo B. Kim
- & David R. Liu
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In vivo genome editing using Staphylococcus aureus Cas9
The physical size of the commonly used Cas9 from Streptococcus pyogenes poses challenges for CRISPR-Cas genome editing systems that use the adeno-associated virus as a delivery vehicle; here, smaller Cas9 orthologues are characterized, and Cas9 from Staphylococcus aureus allowed targeting of the cholesterol regulatory gene Pcsk9 in the mouse liver.
- F. Ann Ran
- , Le Cong
- & Feng Zhang
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Letter |
Promoterless gene targeting without nucleases ameliorates haemophilia B in mice
Promoterless recombinant adeno-associated virus is used without nucleases to target the human coagulation factor IX gene to the liver-expressed albumin locus in haemophilia B mice, with an on-target integration into ∼0.5% of the albumin alleles in hepatocytes; stable F9 plasma levels at 7–20% of normal were obtained, leading to normal coagulation times in treated factor-IX-deficient mice.
- A. Barzel
- , N. K. Paulk
- & M. A. Kay
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Targeted genome editing in human repopulating haematopoietic stem cells
The feasibility of targeted genome editing in human haematopoietic stem cells is demonstrated; the study overcomes previously existing barriers by tailoring delivery platforms and culture conditions.
- Pietro Genovese
- , Giulia Schiroli
- & Luigi Naldini
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Article |
Towards germline gene therapy of inherited mitochondrial diseases
Mutations in mitochondrial DNA cause a wide range of disorders in humans, with a high prevalence; here it is shown that the nucleus of an affected woman’s egg could be inserted into healthy donor egg cytoplasm by spindle transfer, allowing the birth of healthy offspring.
- Masahito Tachibana
- , Paula Amato
- & Shoukhrat Mitalipov
Durable and efficient gene silencing in vivo by hit-and-run epigenome editing