Preclinical evaluation of AGT mRNA replacement therapy for primary hyperoxaluria type I disease
Taihua Yang, Jiahao Ge, Lei Huang, Xinye Zhu, D. Zhang, Siyuan Tang, Jie Zhao, Yiyangzi Ma, Mei Long, Xiaochen Bo, Jie Li, Yiqing Zhang, Qinggong Yuan, Amar Deep Sharma, Michael Ott, Hongquan Geng, Yicheng Zhao, Liang Zhang, Haifa Shen, Hangwen Li, Dali Li, Ping Wan, Qiang Xia
Abstract
Primary hyperoxaluria type 1 (PH1) is a rare inherited liver disorder caused by alanine glyoxylate aminotransferase (AGT) dysfunction, leading to accumulation of glyoxylate which is then converted into oxalate. Excessive oxalate results in kidney damage due to deposition of oxalate crystals. We have developed an mRNA-based protein replacement therapy for PH1 to restore normal glyoxylate to glycine metabolism. Sequence optimized human AGT mRNA ( hAGT mRNA) was encapsulated in lipopolyplex (LPP) and produced functional AGT enzyme in peroxisomes. Pharmacokinetics and pharmacodynamics (PK/PD) were evaluated in vitro and in vivo. PK demonstrated that AGT mRNA and AGT protein maintained high expression levels for up to 48 hours. A single 2 mg/kg dose in Agxt Q84 −/− rats achieved a 70% reduction in urinary oxalate. Toxicological assessment identified the highest nonserious toxic dose (HNSTD) as 2 mg/kg. These findings affirm the efficacy and safety of hAGT mRNA/LPP and support its clinical application in PH1 treatment.