Correction of a pathogenic gene mutation in human embryos

@article{Ma2017CorrectionOA,
  title={Correction of a pathogenic gene mutation in human embryos},
  author={Hong Ma and Nuria Marti-Gutierrez and Sang-Wook Park and Jun Wu and Yeonmi Lee and Keiichiro Suzuki and Amy Koski and Dong-mei Ji and Tomonari Hayama and Riffat Ahmed and Hayley Darby and Crystal M. Van Dyken and Ying Li and Eunju Kang and A Reum Park and Daesik Kim and Sang-Tae Kim and Jianhui Gong and Ying Gu and Xun Xu and David E. Battaglia and Sacha A. Krieg and David M. Lee and D. Wu and Don P Wolf and Stephen B. Heitner and Juan Carlos Izpisua Belmonte and Paula Amato and Jin-Soo Kim and Sanjiv Kaul and Shoukhrat M Mitalipov},
  journal={Nature},
  year={2017},
  volume={548},
  pages={413-419}
}
Genome editing has potential for the targeted correction of germline mutations. [] Key Result Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, we were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations…
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TLDR
The importance of further basic research to assess the safety of genome editing techniques in human embryos will inform debates about the potential clinical use of this technology, and are consistent with recent findings indicating complexity at on-target sites following CRISPR-Cas9 genome editing.
Frequent loss-of-heterozygosity in CRISPR-Cas9-edited early human embryos
TLDR
The importance of further basic research to assess the safety of genome editing techniques in human embryos will inform debates about the potential clinical use of this technology, as well as consistent with recent findings indicating complexity at on-target sites following CRISPR-Cas9 genome editing.
Correction of the Marfan Syndrome Pathogenic FBN1 Mutation by Base Editing in Human Cells and Heterozygous Embryos
Correction of a Recessive Genetic Defect by CRISPR-Cas9-Mediated Endogenous Repair.
TLDR
Proof of principle that homology-directed recombination can be exploited in compound heterozygote cells to correct a genetic defect without exogenous templates is given.
Reading frame restoration at the EYS locus, and allele-specific chromosome removal after Cas9 cleavage in human embryos
TLDR
Evaluated repair outcomes of a Cas9-induced double-strand break introduced on the paternal chromosome at the EYS locus show that the most common repair outcome is microhomology-mediated end joining, which occurs during the first cell cycle in the zygote, leading to embryos with non-mosaic restoration of the reading frame.
FREQUENT GENE CONVERSION IN HUMAN EMBRYOS INDUCED BY DOUBLE STRAND BREAKS
TLDR
It is reported that DSBs selectively induced on a mutant allele in heterozygous human embryos are repaired by gene conversion using an intact wildtype homolog as a template in up to 40% of targeted embryos.
Allele-specific genome editing using CRISPR-Cas9 causes off-target mutations in diploid yeast
TLDR
There is an up to 99-fold lower gene editing efficiency when editing individual heterozygous loci in the yeast genome due to Cas9-mediated loss of heterozygosity, which could be particularly deleterious for human gene therapy and for cancer treatment.
Super-Mendelian inheritance mediated by CRISPR/Cas9 in the female mouse germline
TLDR
This work utilizes an active genetic “CopyCat” element embedded in the mouse Tyrosinase gene to detect genotype conversions after Cas9 activity in the embryo and in the germline and demonstrates that the CRISPR/Cas9 gene drive mechanism can be implemented to simplify complex genetic crosses in laboratory mice.
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