What type of study is this?

This is a Cohort Study study (also classified as: Experimental Study).

September 12, 2025Open Access

Advancing Gene Therapy for Phenylketonuria: From Precision Editing to Clinical Translation

Key Points

Gene therapy shows promise for treating phenylketonuria by addressing its genetic causes directly.
Use of adenine base editors and lipid nanoparticles demonstrates effective gene editing in preclinical studies.
Challenges remain in translating these advanced therapies into practical, safe, and effective treatments for patients.
Ongoing research aims to enhance the safety and efficacy of gene therapy approaches to improve patient outcomes.

Abstract

Phenylketonuria (PKU) is an inherited disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene that result in the amino acid phenylalanine (Phe) building up in the blood. Current therapies suggest low-Phe dietary management and (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) therapy, which are limited in efficacy and require lifelong treatment. Recent advances in gene therapy, including gene editing and viral-mediated gene delivery, produce therapeutic effects. Advancements in gene editing technologies, notably adenine base editors (ABEs) and CRISPR-based systems, in conjunction with enhanced delivery methods such as lipid nanoparticles (LNPs) and recombinant viruses, have demonstrated substantial promise in preclinical studies. This review details the pathophysiology of PKU treatment, and progress in preclinical and clinical gene therapy strategies. Emphasis is on adenine base editing using LNPs, recombinant adeno-associated virus (rAAV)-mediated gene transfer, and the translational challenges associated with these technologies. We also discuss future directions for therapeutic reach and ensuring long-term safety and efficacy.

Advancing Gene Therapy for Phenylketonuria: From Precision Editing to Clinical Translation

Key Points

Abstract

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