Figure 5.
Prime editing to correct PAH c.1222C>T variant in humanized mice
(A) Changes in blood phenylalanine levels in homozygous PKU mice after treatment with 8 × 1011 vg AAV dose (n = 4 animals) or with 4 × 1011 vg AAV dose (n = 3 animals); concentrations at various timepoints up to 5 weeks after treatment were compared to concentrations in untreated homozygous PKU control (n = 3 animals) and untreated heterozygous non-PKU control (n = 3 animals) age-matched (6 weeks of age) colony mates (one blood sample per timepoint).
(B) Changes in blood phenylalanine concentrations in homozygous PKU mice after treatment with 8 × 1011 vg AAV dose (n = 3 animals). Concentrations at various timepoints up to 5 weeks after treatment to were compared to concentrations in untreated heterozygous non-PKU control (n = 2 animals) age-matched (10 weeks of age) colony mates (one blood sample per timepoint).
(C) Changes in blood phenylalanine concentrations in compound-heterozygous PKU mice after treatment with 1 × 1012 vg AAV dose (n = 3 animals). Concentrations at various timepoints up to 5 weeks after treatment were compared to concentrations in untreated heterozygous non-PKU control (n = 2 animals) age-matched (6 weeks of age) colony mates (one blood sample per timepoint).
(D) Corrective PAH c.1222C>T editing (determined from genomic DNA) in the whole liver (mean value from eight liver samples) in each of the treated groups of mice. For compound-heterozygous mice, each displayed number is the estimated percentage of edited c.1222C>T alleles (editable alleles).
(E) Standard CRISPResso output for a liver sample from the treated homozygous PKU mouse with the highest level of editing. Lines in graphs = mean values.