Correction of a pathogenic gene mutation in human embryos

Published on Aug 1, 2017in Nature 41.58
· DOI :10.1038/nature23305
Hong Ma27
Estimated H-index: 27
(Oregon National Primate Research Center),
Nuria Marti-Gutierrez1
Estimated H-index: 1
(Oregon Health & Science University)
+ 28 AuthorsShoukhrat Mitalipov36
Estimated H-index: 36
Abstract
Genome editing could be applied to correct disease-causing mutations in human embryos, but concerns about efficacy and safety are paramount. Shoukhrat Mitalipov and colleagues use CRISPRCas9 to correct a heritable cardiomyopathy mutation in human embryos. By optimizing the experimental conditions, the authors show very reduced mosaicism, and report that for this heterozygous mutation, CRISPRCas9-induced breaks seem to be preferentially repaired using the wild-type allele as a template in human embryos. The results advance our understanding of the promises and challenges of editing the human germline.
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  • Citations (238)
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References48
Published on Dec 1, 2015in Gene 2.50
Lucie Carrier42
Estimated H-index: 42
(University of Hamburg),
Giulia Mearini15
Estimated H-index: 15
(University of Hamburg)
+ 1 AuthorsFriederike Cuello6
Estimated H-index: 6
(University of Hamburg)
Abstract More than 350 individual MYPBC3 mutations have been identified in patients with inherited hypertrophic cardiomyopathy (HCM), thus representing 40–50% of all HCM mutations, making it the most frequently mutated gene in HCM. HCM is considered a disease of the sarcomere and is characterized by left ventricular hypertrophy, myocyte disarray and diastolic dysfunction. MYBPC3 encodes for the thick filament associated protein cardiac myosin-binding protein C (cMyBP-C), a signaling node in card...
41 Citations Source Cite
Published on Oct 24, 2012in Nature 41.58
Masahito Tachibana14
Estimated H-index: 14
(Oregon Health & Science University),
Paula Amato20
Estimated H-index: 20
(Oregon Health & Science University)
+ 17 AuthorsHyo Sang Lee6
Estimated H-index: 6
(Oregon Health & Science University)
Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases and are maternally inherited through the egg’s cytoplasm. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST; also called spindle–chromosomal complex transfer). Of 106 human oocytes donated for research, 65 were subjected to reciprocal ST and 33 served as controls. Fertilization rate in ST oocytes (73%) was similar to controls (75%); however, a significant portion of S...
208 Citations Source Cite
Published on Feb 1, 2014in Cell 31.40
Yuyu Niu15
Estimated H-index: 15
,
Bin Shen14
Estimated H-index: 14
(National Resource Center)
+ 25 AuthorsWei Li10
Estimated H-index: 10
(Chinese Academy of Sciences)
Summary Monkeys serve as important model species for studying human diseases and developing therapeutic strategies, yet the application of monkeys in biomedical researches has been significantly hindered by the difficulties in producing animals genetically modified at the desired target sites. Here, we first applied the CRISPR/Cas9 system, a versatile tool for editing the genes of different organisms, to target monkey genomes. By coinjection of Cas9 mRNA and sgRNAs into one-cell-stage embryos, w...
566 Citations Source Cite
Published on Feb 15, 2013in Science 41.06
Prashant Mali28
Estimated H-index: 28
(Harvard University),
Luhan Yang16
Estimated H-index: 16
(Harvard University)
+ 5 AuthorsGeorge M Church G M132
Estimated H-index: 132
(Wyss Institute for Biologically Inspired Engineering)
Bacteria and archaea have evolved adaptive immune defenses, termed clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems, that use short RNA to direct degradation of foreign nucleic acids. Here, we engineer the type II bacterial CRISPR system to function with custom guide RNA (gRNA) in human cells. For the endogenous AAVS1 locus, we obtained targeting rates of 10 to 25% in 293T cells, 13 to 8% in K562 cells, and 2 to 4% in induced pluripotent stem cel...
4,240 Citations Source Cite
Published on Dec 1, 2014in Nature Communications 12.35
Jong Min Kim21
Estimated H-index: 21
,
Daesik Kim20
Estimated H-index: 20
+ 1 AuthorsJin-Soo Kim51
Estimated H-index: 51
Cas9 RNA-guided engineered nucleases (RGENs) induce site-specific DNA cleavages in cultured cells and organisms and are used widely as genome-editing tools. Here, the authors develop an RGEN-based technology to genotype both RGEN-induced mutations and cancer-associated mutations in human cell lines.
57 Citations Source Cite
Published on May 1, 2015in Nature Biotechnology 35.72
Takeshi Maruyama14
Estimated H-index: 14
(Massachusetts Institute of Technology),
Stephanie K. Dougan24
Estimated H-index: 24
(Massachusetts Institute of Technology)
+ 3 AuthorsHidde L. Ploegh113
Estimated H-index: 113
(Massachusetts Institute of Technology)
The efficiency of homologous recombination-based Cas9 genome editing is increased by inhibiting non-homologous end joining.
430 Citations Source Cite
Published on Dec 1, 2015in Genome Biology 13.21
Tomomi Aida11
Estimated H-index: 11
(Tokyo Medical and Dental University),
Keiho Chiyo1
Estimated H-index: 1
(Tokyo Medical and Dental University)
+ 7 AuthorsKohichi Tanaka49
Estimated H-index: 49
(Tokyo Medical and Dental University)
Although the CRISPR/Cas system has enabled one-step generation of knockout mice, low success rates of cassette knock-in limit its application range. Here we show that cloning-free, direct nuclear delivery of Cas9 protein complex with chemically synthesized dual RNAs enables highly efficient target digestion, leading to generation of knock-in mice carrying a functional cassette with up to 50% efficiency, compared with just 10% by a commonly used method consisting of Cas9 mRNA and single guide RNA...
115 Citations Source Cite
Published on Jan 1, 2011in Nature Biotechnology 35.72
James Robinson84
Estimated H-index: 84
(Massachusetts Institute of Technology),
Helga Thorvaldsdottir10
Estimated H-index: 10
(Massachusetts Institute of Technology)
+ 4 AuthorsJill P. Mesirov70
Estimated H-index: 70
(Massachusetts Institute of Technology)
Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgea...
3,777 Citations Source Cite
Published on Sep 1, 2013in Nature Biotechnology 35.72
Patrick Hsu15
Estimated H-index: 15
,
Douglas Scott96
Estimated H-index: 96
+ 11 AuthorsOphir Shalem18
Estimated H-index: 18
Analyses of the determinants of the specificity of Cas9 nuclease provide rules for selecting optimal target sites.
1,894 Citations Source Cite
Published on Jan 1, 1990in Nucleic Acids Research 11.56
Thomas D. Schneider38
Estimated H-index: 38
,
R M Stephens1
Estimated H-index: 1
A graphical method is presented for displaying the patterns in a set of aligned sequences. The characters representing the sequence are stacked on top of each other for each position in the aligned sequences. The height of each letter is made proportional to its frequency, and the letters are sorted so the most common one is on top. The height of the entire stack is then adjusted to signify the information content of the sequences at that position. From these 'sequence logos', one can determine ...
2,240 Citations Source Cite
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  • Citations (238)
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Cited By238
Published on Oct 1, 2017in The Lancet 53.25
Giulio Cossu68
Estimated H-index: 68
(Manchester Academic Health Science Centre),
Martin A. Birchall33
Estimated H-index: 33
(University College London)
+ 16 AuthorsSteve Morris16
Estimated H-index: 16
(University College London)
In this Commission, we argue that a combination of poor quality science, unclear funding models, unrealistic hopes, and unscrupulous private clinics threatens regenerative medicine's social licence to operate. If regenerative medicine is to shift from mostly small-scale bespoke experimental interventions into routine clinical practice, substantial rethinking of the social contract that supports such research and clinical practice in the public arena will be required. For decades, stem cell thera...
19 Citations Source Cite
Published on Aug 1, 2017in Nature 41.58
Heidi Ledford Hkl22
Estimated H-index: 22
5 Citations Source Cite
Published on Aug 1, 2017in Nature 41.58
Nerges Winblad1
Estimated H-index: 1
,
Fredrik Lanner19
Estimated H-index: 19
The gene-editing technology CRISPR–Cas has been used in human embryos grown in vitro to correct a disease-associated mutation. The introduction of editing components at fertilization aided repair efficiency. See Article p.413
2 Citations Source Cite
José Luis Capelo29
Estimated H-index: 29
,
Hugo M. Santos17
Estimated H-index: 17
+ 1 AuthorsSusana Jorge3
Estimated H-index: 3
Source Cite
Published on Aug 30, 2017in Science Translational Medicine 16.71
Leah C. Byrne (University of Pittsburgh)
Researchers have edited the genome of human embryos to correct dominant myocardial disease.
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Published on Aug 31, 2017in Nature 41.58
Ewen Callaway Ec17
Estimated H-index: 17
3 Citations Source Cite
Published on Aug 1, 2018in Nature 41.58
Dieter Egli34
Estimated H-index: 34
(Columbia University),
Michael V. Zuccaro1
Estimated H-index: 1
(Columbia University)
+ 3 AuthorsMaria Jasin77
Estimated H-index: 77
(Memorial Sloan Kettering Cancer Center)
Many human diseases have an underlying genetic component. The development and application of methods to prevent the inheritance of damaging mutations through the human germline could have significant health benefits, and currently include preimplantation genetic diagnosis and carrier screening. Ma et al. take this a step further by attempting to remove a disease mutation from the human germline through gene editing (1). They assert the following advances: (i) the correction of a pathogenic gene ...
18 Citations Source Cite
Published on Sep 1, 2017in Cell Stem Cell 23.29
Xiao-Jiang Li61
Estimated H-index: 61
(Emory University),
Zhuchi Tu7
Estimated H-index: 7
(Jinan University)
+ 1 AuthorsLi Shihua76
Estimated H-index: 76
(Emory University)
Off-target effects and mosaicism are major concerns for applying CRISPR-Cas9 to correct genetic mutations. A recent article in Nature by Ma et al. (2017) uses an elegant CRISPR-Cas9 approach that repairs a genetic mutation in human embryos with negligible mosaicism and no off-target effects, bringing this editing tool closer to clinical application.
1 Citations Source Cite
Published on Nov 1, 2017in Pharmacological Research 4.90
Patrick J. Collins2
Estimated H-index: 2
(Amgen),
Christopher M. Hale13
Estimated H-index: 13
(Amgen),
Han Xu1
Estimated H-index: 1
(Amgen)
Abstract Within the short few years since the report of its application in precise genome editing, CRISPR technology has become the method of choice to modify and modulate gene expression in biomedical research and therapeutic development. Subsequently, a variety of research, diagnostic, and therapeutic tools have been developed based upon CRISPR’s mechanism of action. Such tools have helped to deepen the understanding of fundamental biology and broaden the horizon in the search for treatments f...
3 Citations Source Cite
Published on Sep 1, 2017in Hastings Center Report 1.47
Andrew W. Torrance4
Estimated H-index: 4
Source Cite