*8.2. Nitisinone*

Nitisinone (NTBC, Orfadin®, Swedish Orphan Biovitrum, Stockholm, Sweden) has been an effective treatment for HT1 since 1992. It inhibits an enzyme, 4-hydroxyphenylpyruvate dioxygenase (HPPD), upstream of *FAH*. Nitisinone is a well-tolerated drug, but its drawbacks include the development of corneal lesions in rats, transient thrombocytopenia, and leucopenia [104,112]. Recently, clustered regularly interspaced short palindromic repeats (CRISPR)—CRISPR-associated (Cas) systems mediated gene correction has been demonstrated in vivo and ex vivo. In a mouse model of HT1, 1 of 250 liver cells was corrected by the hydrodynamic injection of a donor oligonucleotide and a plasmid co-expressing gRNA and Cas9. However, NTBC supplementation with the CRISPR components showed better therapeutic results in mice than either treatment alone [113]. In ex vivo experiments, hepatocyte cells were collected from individual HT1 mouse models, corrected using CRISPR/Cas9 components, and implanted back to the organism. That method of replacing the mutated genotype has high efficiency, but it still requires cycles of NTBC treatment [114].
