Amelioration of metabolic and behavioral defects through base editing in the Pah^R408W phenylketonuria mouse model.

ABSTRACT: Phenylketonuria (PKU) is a liver metabolic disorder mainly caused by a deficiency of the hepatic phenylalanine hydroxylase (PAH) enzyme activity, often leading to severe brain function impairment in patients if untreated or if treatment is delayed. In this study, we utilized dual-AAV8 vectors to deliver a near PAM-less adenine base editor variant, known as ABE8e-SpRY, to treat the Pah^R408W PKU mouse model carrying a frequent R408W mutation in the Pah gene. Our findings revealed that a single intravenous injection in adult mice and a single intraperitoneal injection in neonatal mice resulted in 19.1%-34.6% A-to-G editing efficiency at the pathogenic mutation site with minimal bystander edits. Furthermore, the dual-AAV8-treated mice exhibited reduced blood Phe levels to below the

SUBMITTER: Yin S 

PROVIDER: S-EPMC11764323 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature