原发性高草酸尿
草酸钙
肾钙质沉着症
体内
乙醛酸循环
生物
肾
突变体
分子生物学
基因
遗传学
生物化学
内分泌学
泌尿系统
酶
作者
Zhoutong Chen,D. Zhang,Rui Zheng,Lei Yang,Yanyan Huo,Dan Zhang,Xiaoliang Fang,Yueyan Li,Guofeng Xu,Dali Li,Hui Geng
标识
DOI:10.1016/j.kint.2023.11.029
摘要
Primary hyperoxaluria type 1 (PH1) is a childhood-onset autosomal recessive disease, characterized by nephrocalcinosis, multiple recurrent urinary calcium oxalate stones, and a high risk of progressive kidney damage. PH1 is caused by inherent genetic defects of the alanine glyoxylate aminotransferase (AGXT) gene. The in vivo repair of disease-causing genes was exceedingly inefficient before the invention of base editors which can efficiently introduce precisely targeted base alterations without double-strand DNA breaks. Adenine base editor (ABE) can precisely convert A·T to G·C with the assistance of specific guide RNA. Here, we demonstrated that systemic delivery of dual adeno-associated virus encoding a split-ABE8e could artificially repair 13% of the pathogenic allele in AgxtQ84X rats, a model of PH1, alleviating the disease phenotype. Specifically, ABE treatment partially restored the expression of alanine-glyoxylate-aminotransferase (AGT), reduced endogenous oxalate synthesis and alleviated calcium oxalate crystal deposition. Western blot and immunohistochemistry confirmed that ABE8e treatment restored AGT protein expression in hepatocytes. Moreover, the precise editing efficiency in the liver remained stable six months after treatment. Thus, our findings provided a prospect of in vivo base editing as a personalized and precise medicine for PH1 by directly correcting the mutant Agxt gene.
科研通智能强力驱动
Strongly Powered by AbleSci AI