Efficient in vivo prime editing corrects the most frequent phenylketonuria variant, associated with high unmet medical need.
Am J Hum Genet
; 110(12): 2003-2014, 2023 Dec 07.
Article
em En
| MEDLINE
| ID: mdl-37924808
ABSTRACT
The c.1222C>T (p.Arg408Trp) variant in the phenylalanine hydroxylase gene (PAH) 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 individuals harboring at least one c.1222C>T variant experience chronic, severe Phe elevations and do not comply with Phe monitoring guidelines. Motivated by these findings, we generated an edited c.1222C>T hepatocyte cell line and humanized c.1222C>T 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 strategy involving prime editing as a potential treatment for a large proportion of individuals with PKU.
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Base de dados:
MEDLINE
Assunto principal:
Fenilalanina Hidroxilase
/
Fenilcetonúrias
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article