CRISPR/Cas9-mediated genome editing via postnatal administration of AAV vector cures haemophilia B mice View Full Text


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Article Info

DATE

2017-06-23

AUTHORS

Tsukasa Ohmori, Yasumitsu Nagao, Hiroaki Mizukami, Asuka Sakata, Shin-ichi Muramatsu, Keiya Ozawa, Shin-ichi Tominaga, Yutaka Hanazono, Satoshi Nishimura, Osamu Nureki, Yoichi Sakata

ABSTRACT

Haemophilia B, a congenital haemorrhagic disease caused by mutations in coagulation factor IX gene (F9), is considered an appropriate target for genome editing technology. Here, we describe treatment strategies for haemophilia B mice using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system. Administration of adeno-associated virus (AAV) 8 vector harbouring Staphylococcus aureus Cas9 (SaCas9) and single guide RNA (sgRNA) to wild-type adult mice induced a double-strand break (DSB) at the target site of F9 in hepatocytes, sufficiently developing haemophilia B. Mutation-specific gene editing by simultaneous induction of homology-directed repair (HDR) sufficiently increased FIX levels to correct the disease phenotype. Insertion of F9 cDNA into the intron more efficiently restored haemostasis via both processes of non-homologous end-joining (NHEJ) and HDR following DSB. Notably, these therapies also cured neonate mice with haemophilia, which cannot be achieved with conventional gene therapy with AAV vector. Ongoing haemophilia therapy targeting the antithrombin gene with antisense oligonucleotide could be replaced by SaCas9/sgRNA-expressing AAV8 vector. Our results suggest that CRISPR/Cas9-mediated genome editing using an AAV8 vector provides a flexible approach to induce DSB at target genes in hepatocytes and could be a good strategy for haemophilia gene therapy. More... »

PAGES

4159

References to SciGraph publications

  • 2013-08-11. High-throughput profiling of off-target DNA cleavage reveals RNA-programmed Cas9 nuclease specificity in NATURE BIOTECHNOLOGY
  • 2015-04-01. In vivo genome editing using Staphylococcus aureus Cas9 in NATURE
  • 2009-11-25. A modified thrombin generation test for investigating very low levels of factor VIII activity in hemophilia A in INTERNATIONAL JOURNAL OF HEMATOLOGY
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  • 2013-09-27. Cas9 as a versatile tool for engineering biology in NATURE METHODS
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  • Journal

    TITLE

    Scientific Reports

    ISSUE

    1

    VOLUME

    7

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41598-017-04625-5

    DOI

    http://dx.doi.org/10.1038/s41598-017-04625-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1086118219

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28646206


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