CRISPR RNA-guided FokI nucleases repair a PAH variant in a phenylketonuria model View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-12

AUTHORS

Yi Pan, Nan Shen, Sabine Jung-Klawitter, Christian Betzen, Georg F Hoffmann, Jörg D Hoheisel, Nenad Blau

ABSTRACT

The CRISPR/Cas9 system is a recently developed genome editing technique. In this study, we used a modified CRISPR system, which employs the fusion of inactive Cas9 (dCas9) and the FokI endonuclease (FokI-dCas9) to correct the most common variant (allele frequency 21.4%) in the phenylalanine hydroxylase (PAH) gene - c.1222C>T (p.Arg408Trp) - as an approach toward curing phenylketonuria (PKU). PKU is the most common inherited diseases in amino acid metabolism. It leads to severe neurological and neuropsychological symptoms if untreated or late diagnosed. Correction of the disease-causing variants could rescue residual PAH activity and restore normal function. Co-expression of a single guide RNA plasmid, a FokI-dCas9-zsGreen1 plasmid, and the presence of a single-stranded oligodeoxynucleotide in PAH_c.1222C>T COS-7 cells - an in vitro model for PKU - corrected the PAH variant and restored PAH activity. Also in this system, the HDR enhancer RS-1 improved correction efficiency. This proof-of-concept indicates the potential of the FokI-dCas9 system for precision medicine, in particular for targeting PKU and other monogenic metabolic diseases. More... »

PAGES

35794

References to SciGraph publications

  • 2014-06. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype in NATURE BIOTECHNOLOGY
  • 2014-04. CRISPR-Cas systems for editing, regulating and targeting genomes in NATURE BIOTECHNOLOGY
  • 2014-02. E-CRISP: fast CRISPR target site identification in NATURE METHODS
  • 2016-04. Precision Medicine: Genetic Repair of Retinitis Pigmentosa in Patient-Derived Stem Cells in SCIENTIFIC REPORTS
  • 2015-09. Generation of mutant mice via the CRISPR/Cas9 system using FokI-dCas9 in SCIENTIFIC REPORTS
  • 2013-09. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells in NATURE BIOTECHNOLOGY
  • 1975-12. Determination of Phenylalanine Hydroxylase Activity in Patients with Phenylketonuria and Hyperphenylalaninemia in PEDIATRIC RESEARCH
  • 2016-01-28. RS-1 enhances CRISPR/Cas9- and TALEN-mediated knock-in efficiency in NATURE COMMUNICATIONS
  • 2015-05. Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining in NATURE BIOTECHNOLOGY
  • 2014-07. Genome-wide analysis reveals characteristics of off-target sites bound by the Cas9 endonuclease in NATURE BIOTECHNOLOGY
  • 2014-04. Efficient genome modification by CRISPR-Cas9 nickase with minimal off-target effects in NATURE METHODS
  • 2014-06. Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification in NATURE BIOTECHNOLOGY
  • 2014-06. Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing in NATURE BIOTECHNOLOGY
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/srep35794

    DOI

    http://dx.doi.org/10.1038/srep35794

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/27786189


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