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Publication : Rapid and definitive treatment of phenylketonuria in variant-humanized mice with corrective editing.

First Author  Brooks DL Year  2023
Journal  Nat Commun Volume  14
Issue  1 Pages  3451
PubMed ID  37301931 Mgi Jnum  J:344273
Mgi Id  MGI:7491147 Doi  10.1038/s41467-023-39246-2
Citation  Brooks DL, et al. (2023) Rapid and definitive treatment of phenylketonuria in variant-humanized mice with corrective editing. Nat Commun 14(1):3451
abstractText  Phenylketonuria (PKU), an autosomal recessive disorder caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene, results in the accumulation of blood phenylalanine (Phe) to neurotoxic levels. Current dietary and medical treatments are chronic and reduce, rather than normalize, blood Phe levels. Among the most frequently occurring PAH variants in PKU patients is the P281L (c.842C>T) variant. Using a CRISPR prime-edited hepatocyte cell line and a humanized PKU mouse model, we demonstrate efficient in vitro and in vivo correction of the P281L variant with adenine base editing. With the delivery of ABE8.8 mRNA and either of two guide RNAs in vivo using lipid nanoparticles (LNPs) in humanized PKU mice, we observe complete and durable normalization of blood Phe levels within 48 h of treatment, resulting from corrective PAH editing in the liver. These studies nominate a drug candidate for further development as a definitive treatment for a subset of PKU patients.
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