*8.4. Gene Therapy*

Gene therapy is a promising technique for the treatment of PKU and has been studied by several researchers. Recently, a recombinant adeno-associated virus (rAAV) containing the *PAH* gene was delivered to a mouse model of PKU. But the rAAV vector could not permanently correct liver PAH because the vector was not integrated into the genome of the hepatocytes, leading to loss of the vector during subsequent hepatocyte regeneration. When the vector containing *PAH*- and co-factor-synthesizing genes was injected into muscle, it was able to metabolize Phe to Tyr, but low gene transfer means that this approach needs further improvement [118,119]. Inactive Cas9 (dCas9) fused with the *FokI* endonuclease (*FokI*-dCas9) has recently been used to correct the p.Arg408Trp mutation in the *PAH* gene. The frequency of the corrected allele was 21.4%, making *FokI*-dCas9 a promising strategy to treat PKU [120]. Several laboratories have achieved a certain degree of success in correcting the PAH deficiencies, however none has progressed to human trials yet.
