| First Author | Brooks DL | Year | 2023 |
| Journal | Am J Hum Genet | Volume | 110 |
| Issue | 12 | Pages | 2003-2014 |
| PubMed ID | 37924808 | Mgi Jnum | J:344302 |
| Mgi Id | MGI:7568683 | Doi | 10.1016/j.ajhg.2023.10.005 |
| Citation | Brooks DL, et al. (2023) 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 |
| abstractText | 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. |
