Gene Therapy and Enzyme‑Based Strategies for the Future Treatment of Phenylketonuria (PKU)

Phenylketonuria (PKU) is a well‑characterized inborn error of metabolism caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to impaired phenylalanine degradation and neurotoxic accumulation of this amino acid. Although dietary restriction of phenylalanine remains the cornerstone of management, long‑term adherence is difficult and metabolic control is often suboptimal. As a result, substantial research efforts have shifted toward disease‑modifying and potentially curative interventions. This review synthesizes recent advances in gene‑based and enzyme‑based therapeutic strategies for PKU, drawing on findings from preclinical studies, early clinical trials, and emerging biotechnology platforms. We first outline progress in gene therapy approaches, including adeno‑associated virus (AAV), mediated hepatic PAH gene delivery, lentiviral and non‑viral systems, and next‑generation genome editing technologies such as CRISPR/Cas۹, base editing, and prime editing. Key developments related to vector design, delivery efficiency, durability of expression, and safety considerations are critically examined. We then evaluate enzyme‑based modalities, focusing on the clinical use of pegvaliase (PEGylated phenylalanine ammonia lyase), as well as efforts to engineer more stable, less immunogenic enzyme variants, and explore encapsulated or cell‑based platforms for sustained enzymatic activity. Across both therapeutic domains, we highlight shared challenges, including immune responses, off‑target risks, durability of correction, and barriers to pediatric application. Finally, we discuss future directions, emphasizing the potential for combination approaches and personalized treatment frameworks tailored to specific PAH genotypes. This review aims to provide a comprehensive and integrated overview of emerging molecular therapies for PKU, with a focus on their mechanisms, current limitations, and prospects for clinical translation.

کلیدواژه ها:

Phenylketonuria (PKU) ، Gene Therapy ، Enzyme Replacement Therapy ، Phenylalanine Hydroxylase (PAH) ، Pegvaliase ، Genome Editing