In vivo adenine base editing rescues brain biochemistry and improves motor deficits in a common phenylketonuria variant

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the phenylalanine hydroxylase ( PAH ) gene. Patients are unable to convert the amino acid phenylalanine (Phe) into tyrosine (Tyr), leading to neurotoxic Phe accumulation. Chronically elevated Phe results in intellectual disability, psychiatric disorders, motor impairments, and epilepsy in affected children. Although there are interventions that focus on reducing plasma Phe levels, no curative therapies exist for PKU. Utilizing an adenine base editor (ABE), we demonstrate efficient in vivo corrective editing of hepatocytes in humanized PKU mice homozygous for the common P281L (c.842C>T) variant of PAH. Delivery of the ABE via lipid nanoparticles (LNPs) at four weeks of age resulted in significant reductions in Phe levels in plasma and cortex, as well as increases in cerebral amino acid and neurotransmitter concentrations. Behavioral assessment post-treatment revealed improvements in abnormal motor phenotypes. These data provide increased support for the viability of ABE-based therapeutics as a durable treatment for patients with monogenic metabolic disorders.