Yu Inseon, Jeong Jaemin
Department of Biohealth Convergence, College of Science and Convergence Technology, Seoul Women's University, Seoul 01797, Republic of Korea.
Int J Mol Sci. 2025 Sep 7;26(17):8722. doi: 10.3390/ijms26178722.
Phenylketonuria (PKU) is an inherited disorder caused by mutations in the gene that result in the amino acid phenylalanine (Phe) building up in the blood. Current therapies suggest low- dietary management and (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH) 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.
苯丙酮尿症（PKU）是一种由基因突变引起的遗传性疾病，这些突变会导致血液中氨基酸苯丙氨酸（Phe）积聚。目前的治疗方法包括低苯丙氨酸饮食管理和（6R）-L-赤藓糖-5,6,7,8-四氢生物蝶呤（BH4）治疗，其疗效有限且需要终身治疗。基因治疗的最新进展，包括基因编辑和病毒介导的基因递送，产生了治疗效果。基因编辑技术的进步，特别是腺嘌呤碱基编辑器（ABEs）和基于CRISPR的系统，与脂质纳米颗粒（LNPs）和重组病毒等增强递送方法相结合，在临床前研究中显示出巨大的前景。本综述详细介绍了PKU治疗的病理生理学以及临床前和临床基因治疗策略的进展。重点是使用LNPs进行腺嘌呤碱基编辑、重组腺相关病毒（rAAV）介导的基因转移以及与这些技术相关的转化挑战。我们还讨论了治疗范围的未来方向以及确保长期安全性和有效性的问题。
