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of Pennsylvaniahttps://www.ebi.ac.uk/ena/browser/view/PRJNA1015257The R408W (c.1222C>T, p.Arg408Trp) phenylalanine hydroxylase (PAH) variant is the most frequent cause of phenylketonuria (PKU), the most common inborn error of metabolism. This autosomal recessive disorder is characterized by accumulation of blood phenylalanine (Phe) to neurotoxic levels. Using real-world data, we observed that despite dietary and medical interventions, most PKU patients harboring at least one R408W variant experience chronic, severe Phe elevations and do not comply with Phe monitoring guidelines. Motivated by these findings, we generated an edited R408W hepatocyte cell line and humanized R408W mouse models, with which we demonstrated efficient in vitro and in vivo correction of the variant with prime editing. Delivery via adeno-associated viral (AAV) vectors reproducibly achieved complete normalization of blood Phe levels in PKU mice, with up to 52% whole-liver corrective PAH editing. These studies validate a prime editing strategy as a potential treatment for a large proportion of PKU patients.xref:EuropePMC:PMC10716342ENAfalseEfficient in vivo prime editing corrects the most frequent phenylketonuria variant, associated with high unmet medical need2023-10-282023-10-28PRJNA1015257