Preclinical evaluation of AGT mRNA replacement therapy for primary hyperoxaluria type I disease

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-04-09 DOI:10.1126/sciadv.adt9694

Taihua Yang, Jiahao Ge, Lei Huang, Xinye Zhu, Dexin Zhang, Siyuan Tang, Jie Zhao, Yinhe 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

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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 AgxtQ84^−/− 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.

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.