Application of CRISPR Technology in the Treatment of Phenylketonuria

Abstract

Phenylketonuria (PKU) is an autosomal recessive disorder caused by a pathogenic variant of the phenylalanine hydroxylase (PAH) gene. The pathogenic mechanism involves mutations in the PAH gene leading to the accumulation of phenylalanine (Phe) in the blood to neurotoxic levels, preventing patients from metabolizing phenylalanine normally and thereby affecting the development of the nervous system. Traditional treatment methods primarily consist of adhering to a strict low-phenylalanine diet to reduce the intake of phenylalanine from food, or employing gene therapy techniques to repair or replace the defective PAH gene. The emergence of CRISPR technology in recent years has opened new possibilities for treating genetic diseases, including PKU, especially in gene correction and disease model creation. Gene editing techniques, exemplified by CRISPR-Cas9, theoretically enable the direct modification or repair of defective PAH genes at the DNA level, and this approach holds promise for achieving more precise and permanent genetic repairs. This research begins by introducing the pathogenic mechanism of PKU from a genetic perspective, from the structure to the function of the PAH gene, analyzing the defects caused by its mutations, then discusses the potential of gene therapy using CRISPR technology to correct PAH gene mutations, highlighting new techniques such as prime editing and base editing. This research aims to summarize the current state of CRISPR technology applications in treating PKU, cataloging and evaluating various methods. It introduces new considerations based on existing research and looks forward to future research directions, thereby offering new potential treatments for PKU.