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Towards therapeutic base editing

Published on Oct 1, 2018in Nature Medicine30.641
· DOI :10.1038/s41591-018-0215-3
Huiyun Seo1
Estimated H-index: 1
,
Jin-Soo Kim53
Estimated H-index: 53
(SNU: Seoul National University)
Sources
Abstract
Base editors function in mouse fetuses and in the livers of adult mice to treat a genetic disorder.
  • References (11)
  • Citations (2)
References11
Newest
#1Avery C. Rossidis (Children's Hospital of Philadelphia)H-Index: 3
#2John D. Stratigis (Children's Hospital of Philadelphia)H-Index: 3
Last. William H. Peranteau (Children's Hospital of Philadelphia)H-Index: 24
view all 17 authors...
In utero gene editing has the potential to prenatally treat genetic diseases that result in significant morbidity and mortality before or shortly after birth. We assessed the viral vector–mediated delivery of CRISPR–Cas9 or base editor 3 in utero, seeking therapeutic modification of Pcsk9 or Hpd in wild-type mice or the murine model of hereditary tyrosinemia type 1, respectively. We observed long-term postnatal persistence of edited cells in both models, with reduction of plasma PCSK9 and choles...
29 CitationsSource
#1Maria Paz Zafra (Cornell University)H-Index: 3
#2Emma M. Schatoff (Kettering University)H-Index: 4
Last. Lukas E. Dow (Cornell University)H-Index: 25
view all 18 authors...
The efficiency of base editing is substantially increased by optimizing expression and nuclear localization of the editing enzymes.
49 CitationsSource
#1Seuk-Min RyuH-Index: 4
#2Taeyoung KooH-Index: 15
Last. Jin-Soo KimH-Index: 53
view all 11 authors...
Adenine base editing is used to treat a mouse model of Duchenne muscular dystrophy and to create defined mutations in mouse embryos.
48 CitationsSource
#1Xiaosa LiH-Index: 3
#2Ying WangH-Index: 2
Last. Jia ChenH-Index: 13
view all 12 authors...
A new fusion protein enables precise editing of single bases in A/T-rich regions of the human genome.
70 CitationsSource
#1Nicole M. GaudelliH-Index: 6
#2Alexis C. KomorH-Index: 13
Last. David R. LiuH-Index: 73
view all 7 authors...
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.
457 CitationsSource
#1Kyoungmi KimH-Index: 4
#2Seuk-Min RyuH-Index: 4
Last. Jin-Soo KimH-Index: 53
view all 9 authors...
Mice with targeted point mutations are generated efficiently using Cas9–cytidine deaminase fusions.
145 CitationsSource
#1Y. Bill Kim (Harvard University)H-Index: 2
#2Alexis C. Komor (Harvard University)H-Index: 13
Last. David R. Liu (Broad Institute)H-Index: 73
view all 6 authors...
Genome editing of single bases is made more versatile and accurate with new fusions of mutated Cas9 and cytidine deaminase domains.
197 CitationsSource
#1Keiji Nishida (Kobe University)H-Index: 24
#2Takayuki Arazoe (Kobe University)H-Index: 7
Last. Akihiko Kondo (Kobe University)H-Index: 70
view all 12 authors...
INTRODUCTION To combat invading pathogens, cells develop an adaptive immune response by changing their own genetic information. In vertebrates, the generation of genetic variation (somatic hypermutation) is an essential process for diversification and affinity maturation of antibodies that function to detect and sequester various foreign biomolecules. The activation-induced cytidine deaminase (AID) carries out hypermutation by modifying deoxycytidine bases in the variable region of the immunoglo...
335 CitationsSource
#1Alexis C. KomorH-Index: 13
#2Yongjoo KimH-Index: 7
Last. David R. LiuH-Index: 73
view all 5 authors...
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.
866 CitationsSource
#1Joris A. Veltman (Radboud University Nijmegen)H-Index: 75
#2Han G. Brunner (Radboud University Nijmegen)H-Index: 92
New mutations have long been known to cause genetic disease, but their true contribution to the disease burden can only now be determined using family-based whole-genome or whole-exome sequencing approaches. In this Review we discuss recent findings suggesting that de novo mutations play a prominent part in rare and common forms of neurodevelopmental diseases, including intellectual disability, autism and schizophrenia. De novo mutations provide a mechanism by which early-onset reproductively le...
458 CitationsSource
Cited By2
Newest
#1Jing Zeng (Harvard University)H-Index: 1
#2Yuxuan Wu (ECNU: East China Normal University)H-Index: 4
Last. Qiuming Yao (Harvard University)H-Index: 9
view all 16 authors...
Base editing by nucleotide deaminases linked to programmable DNA-binding proteins represents a promising approach to permanently remedy blood disorders, although its application in engrafting hematopoietic stem cells (HSCs) remains unexplored. In this study, we purified A3A (N57Q)-BE3 base editor for ribonucleoprotein (RNP) electroporation of human-peripheral-blood-mobilized CD34+ hematopoietic stem and progenitor cells (HSPCs). We observed frequent on-target cytosine base edits at the BCL11A er...
1 CitationsSource
#1Julian GrünewaldH-Index: 2
#2Ronghao Zhou (Harvard University)H-Index: 2
Last. J. Keith JoungH-Index: 62
view all 7 authors...
CRISPR-Cas base editor technology enables targeted nucleotide alterations and is being rapidly deployed for research and potential therapeutic applications1,2. The most widely used base editors induce DNA cytosine (C) deamination with rat APOBEC1 (rAPOBEC1) enzyme, which is targeted by a linked Cas protein-guide RNA (gRNA) complex3,4. Previous studies of cytosine base editor (CBE) specificity have identified off-target DNA edits in human cells5,6. Here we show that a CBE with rAPOBEC1 can cause ...
27 CitationsSource
#1Hui YangH-Index: 19
#2LIYixueH-Index: 57
Last. Lars M. Steinmetz (Stanford University)H-Index: 56
view all 8 authors...
Genome editing tools including CRISPR/Cas9 and base editors hold great promise for correcting pathogenic mutations. Unbiased genome-wide off-target effects of the editing in mammalian cells is required before clinical applications, but determination of the extent of off-target effects has been difficult due to the existence of single nucleotide polymorphisms (SNPs) in individuals. Here, we developed a method named GOTI (Genome-wide Off-target analysis by Two-cell embryo Injection) to detect off-...
4 CitationsSource