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    Precise in vivo genome editing via single homology arm donor mediated intron-targeting gene integration for genetic disease correction.

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    Type
    Article
    Authors
    Suzuki, Keiichiro cc
    Yamamoto, Mako
    Hernandez-Benitez, Reyna
    Li, Zhe
    Wei, Christopher
    Soligalla, Rupa Devi
    Aizawa, Emi
    Hatanaka, Fumiyuki
    Kurita, Masakazu
    Reddy, Pradeep cc
    Ocampo, Alejandro
    Hishida, Tomoaki
    Sakurai, Masahiro
    Nemeth, Amy N
    Nuñez Delicado, Estrella
    Campistol, Josep M
    Magistretti, Pierre J. cc
    Guillen, Pedro
    Rodriguez Esteban, Concepcion
    Gong, Jianhui
    Yuan, Yilin
    Gu, Ying
    Liu, Guang-Hui cc
    López-Otín, Carlos cc
    Wu, Jun cc
    Zhang, Kun cc
    Izpisua Belmonte, Juan Carlos
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Date
    2019-08-23
    Embargo End Date
    2020-02-25
    Permanent link to this record
    http://hdl.handle.net/10754/656597
    
    Metadata
    Show full item record
    Abstract
    In vivo genome editing represents a powerful strategy for both understanding basic biology and treating inherited diseases. However, it remains a challenge to develop universal and efficient in vivo genome-editing tools for tissues that comprise diverse cell types in either a dividing or non-dividing state. Here, we describe a versatile in vivo gene knock-in methodology that enables the targeting of a broad range of mutations and cell types through the insertion of a minigene at an intron of the target gene locus using an intracellularly linearized single homology arm donor. As a proof-of-concept, we focused on a mouse model of premature-aging caused by a dominant point mutation, which is difficult to repair using existing in vivo genome-editing tools. Systemic treatment using our new method ameliorated aging-associated phenotypes and extended animal lifespan, thus highlighting the potential of this methodology for a broad range of in vivo genome-editing applications.
    Citation
    Suzuki, K., Yamamoto, M., Hernandez-Benitez, R., Li, Z., Wei, C., Soligalla, R. D., … Izpisua Belmonte, J. C. (2019). Precise in vivo genome editing via single homology arm donor mediated intron-targeting gene integration for genetic disease correction. Cell Research. doi:10.1038/s41422-019-0213-0
    Sponsors
    We are grateful to M. Schwarz and P. Schwarz for administrative help; D. O’Keefe and S. Tsuji for help with manuscript preparation; M. Kay and Z.Y. Chen for sharing experimental materials; J. Naughton and J. Marlett for AAV production; K. Peterson and Y. Gu for helping the measurement of heart rate; U. Manor and K. Diffenderfer for imaging; K. McIntyre for mouse histology processing and J. Li for helping the molecular work; K. Sumiyama for data analysis. M.Y. was partially supported by 2016 Salk Women & Science Special Award. K.S. was supported by JSPS KAKENHI (15K21762 and 18H04036), Takeda Science Foundation, The Uehara Memorial Foundation, National Institutes of Natural Sciences (BS291007), The Sumitomo Foundation (170220), The Naito Foundation, The Kurata Grants (1350), Mochida Memorial Foundation, and The Inamori Foundation. This research was supported by Guangdong Provincial Key Laboratory of Genome Read and Write (No. 2017B030301011), Guangdong Provincial Academician Workstation of BGI Synthetic Genomics (No. 2017B090904014) and Shenzhen Peacock Plan (No. KQTD20150330171505310). J.C.I.B. was supported by The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002), the G. Harold and Leila Y. Mathers Charitable Foundation, NIH (R01HL123755 and 5 DP1 DK113616), The Progeria Research Foundation, The Glenn Foundation, KAUST, The Moxie Foundation, Fundación Dr. Pedro Guillen, AFE and Universidad Católica San Antonio de Murcia (UCAM).
    Publisher
    Springer Nature
    Journal
    Cell research
    DOI
    10.1038/s41422-019-0213-0
    Additional Links
    http://www.nature.com/articles/s41422-019-0213-0
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41422-019-0213-0
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program

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