To test the SpRY-ABE8.8/PAH4 combination in vivo, we used CRISPR-Cas9 targeting in mouse embryos to generate a humanized PKU model with the PAH c.1222C>T (p.Arg408Trp) variant (hereafter referred to as R408W mice) in the C57BL/6J background, in which we replaced a small portion of the endogenous mouse Pah exon 12 with the orthologous human sequence spanning the PAH4 gRNA protospacer/PAM sequences and containing the c.1222C>T variant (Figure S3A). This evidence concerns the gene PAH and phenylketonuria.