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CRISPR RNA-guided FokI nucleases repair a PAH variant in a phenylketonuria model
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CRISPR RNA-guided FokI nucleases repair a PAH variant in a phenylketonuria model
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Journal Article
CRISPR RNA-guided FokI nucleases repair a PAH variant in a phenylketonuria model
2016
Overview
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
Fok
I endonuclease (
Fok
I-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
Fok
I-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
Fok
I-dCas9 system for precision medicine, in particular for targeting PKU and other monogenic metabolic diseases.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 692/4017
/ Animals
/ Cloning
/ Clustered Regularly Interspaced Short Palindromic Repeats
/ CRISPR
/ Deoxyribonucleases, Type II Site-Specific - genetics
/ Deoxyribonucleases, Type II Site-Specific - metabolism
/ Disease
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Mutation
/ Nuclease
/ Phenylalanine 4-monooxygenase
/ Phenylalanine Hydroxylase - genetics
/ Phenylalanine Hydroxylase - metabolism
/ Plasmids
/ Proteins
/ RNA
/ Science
