Background

Phenylketonuria (PKU) is a congenital metabolic disorder caused by a deficiency in the phenylalanine hydroxylase (PAH) gene, which converts the essential amino acid phenylalanine into tyrosine in the liver. If phenylalanine that has not been metabolized accumulates in brain tissue, it causes irreversible cognitive decline and central nervous system damage. While early diagnosis has been established through newborn screening, patients have had to strictly limit high-protein food intake and rely on special medical amino acid formulations for life.

For patients entering adulthood, such dietary management leads to social isolation and a severe decline in quality of life. In clinical settings, the recurrence of neurological deficits in adult patients, whose dietary compliance drops sharply, has been a major challenge. Although enzyme replacement therapies like pegvaliase have been developed, their clinical application has been limited due to the need for frequent subcutaneous injections and the risk of systemic immune side effects, including anaphylaxis. This provided the background for the need for a long-term therapeutic strategy to fundamentally restore PAH expression within liver parenchymal cells.

Key Findings

This study, reported in the New England Journal of Medicine (NEJM), presents the clinical follow-up results of a cohort of adult patients with severe PKU who received a single intravenous administration of an adeno-associated virus (AAV) vector to correct the genetic deficiency. Researchers intravenously administered liver-tropic AAV vectors, combining functional human PAH genes with liver-specific promoters, to adult patients.

During follow-up after the single dose, patients' blood phenylalanine levels dropped from a baseline average of over 1,200 μmol/L to below the clinical safety threshold of 360 μmol/L. Many patients maintained a stable range (120–360 μmol/L) even when attempting to transition to a regular diet starting from the 6-month mark post-treatment. The daily permissible intake of natural protein also increased more than threefold compared to baseline, significantly improving metabolic homeostasis.

Transient increases in liver enzyme levels (ALT/AST) were observed in some administration groups, but stabilized without hepatotoxicity through short-term oral corticosteroid management. The severe systemic allergic reactions commonly reported in previous protein-based therapies were not observed. The clinical data demonstrate that PAH gene expression in liver tissue restores normal enzyme activity, thereby directly resolving the metabolic abnormalities associated with the disease.

Significance and Outlook

This achievement demonstrates the potential to shift the management paradigm of rare metabolic diseases, which were previously bound by dietary therapy, toward a one-time gene delivery therapy. It is expected to alleviate the burden of lifelong strict dietary management and contribute to maintaining cognitive function and preventing neurological complications in adult patients. From the perspective of fundamentally compensating for metabolic pathway deficiencies, it demonstrates prominent advantages over enzyme replacement therapy in terms of treatment convenience and improved long-term compliance.

However, challenges remain before declaring a permanent cure. A representative issue is that re-administration of the same vector is virtually impossible due to neutralizing antibodies generated after AAV vector administration. The dilution of therapeutic gene expression due to hepatocyte division and the achievement of long-term persistence should be verified through additional follow-up studies over several years. High treatment costs and the exclusion of patients with pre-existing antibodies are also challenges to be addressed in the future stage of clinical translation.