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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.

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