Advances in molecular and gene-based therapies for phenylketonuria: Mechanisms, therapeutic strategies, and clinical translation

Phenylketonuria (PKU) is a prototypical inherited metabolic disorder caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene, resulting in toxic accumulation of phenylalanine and progressive neurological impairment. Although lifelong dietary restriction remains the standard of care, suboptimal adherence, nutritional imbalance, and incomplete neuroprotection limit its long-term effectiveness. Recent advances in gene therapy and genome-editing technologies have substantially advanced therapeutic strategies for PKU by enabling restoration of hepatic PAH activity at the molecular level. This review synthesizes the current understanding of PKU pathogenesis and critically evaluates emerging gene-based therapeutic approaches, including CRISPR/Cas9-mediated editing, base editing, prime editing, viral and non-viral gene replacement, and mRNA-based therapies. We further discuss translational challenges related to delivery, safety, durability, and patient stratification, and outline future directions toward personalized and potentially curative interventions.