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

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

doi:10.1126/sciadv.adt9694

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

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^*

^*此作品的通讯作者

生命科学学院

Shanghai Jiao Tong University
Stemirna Therapeutics
Fudan University
Hannover Medical School
China-Japan Union Hospital of Jilin University
Chinese Academy of Sciences
CAS - Shanghai Institute of Organic Chemistry
Shanghai Organ Transplantation and Immune Engineering Technology Research Center

科研成果: 期刊稿件 › 文章 › 同行评审

12 引用（Scopus）

摘要

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.

源语言	英语
文章编号	eadt9694
期刊	Science Advances
卷	11
期	15
DOI	https://doi.org/10.1126/sciadv.adt9694
出版状态	已出版 - 11 4月 2025

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Yang, T., Ge, J., Huang, L., Zhu, X., Zhang, D., Tang, S., Zhao, J., Ma, Y., Long, M., Bo, X., Li, J., Zhang, Y., Yuan, Q., Sharma, A. D., Ott, M., Geng, H., Zhao, Y., Zhang, L., Shen, H., ... Xia, Q. (2025). Preclinical evaluation of AGT mRNA replacement therapy for primary hyperoxaluria type I disease. Science Advances, 11(15), 文章 eadt9694. https://doi.org/10.1126/sciadv.adt9694

@article{209ff84d33364fd89e934839aa428abd,

title = "Preclinical evaluation of AGT mRNA replacement therapy for primary hyperoxaluria type I disease",

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.",

author = "Taihua Yang and Jiahao Ge and Lei Huang and Xinye Zhu and Dexin Zhang and Siyuan Tang and Jie Zhao and Yinhe Ma and Mei Long and Xiaochen Bo and Jie Li and Yiqing Zhang and Qinggong Yuan and Sharma, \{Amar Deep\} and Michael Ott and Hongquan Geng and Yicheng Zhao and Liang Zhang and Haifa Shen and Hangwen Li and Dali Li and Ping Wan and Qiang Xia",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 The Authors, some rights reserved.",

year = "2025",

month = apr,

day = "11",

doi = "10.1126/sciadv.adt9694",

language = "英语",

volume = "11",

journal = "Science Advances",

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Yang, T, Ge, J, Huang, L, Zhu, X, Zhang, D, Tang, S, Zhao, J, Ma, Y, Long, M, Bo, X, Li, J, Zhang, Y, Yuan, Q, Sharma, AD, Ott, M, Geng, H, Zhao, Y, Zhang, L, Shen, H, Li, H, Li, D, Wan, P & Xia, Q 2025, 'Preclinical evaluation of AGT mRNA replacement therapy for primary hyperoxaluria type I disease', Science Advances, 卷 11, 号码 15, eadt9694. https://doi.org/10.1126/sciadv.adt9694

TY - JOUR

T1 - Preclinical evaluation of AGT mRNA replacement therapy for primary hyperoxaluria type I disease

AU - Yang, Taihua

AU - Ge, Jiahao

AU - Huang, Lei

AU - Zhu, Xinye

AU - Zhang, Dexin

AU - Tang, Siyuan

AU - Zhao, Jie

AU - Ma, Yinhe

AU - Long, Mei

AU - Bo, Xiaochen

AU - Li, Jie

AU - Zhang, Yiqing

AU - Yuan, Qinggong

AU - Sharma, Amar Deep

AU - Ott, Michael

AU - Geng, Hongquan

AU - Zhao, Yicheng

AU - Zhang, Liang

AU - Shen, Haifa

AU - Li, Hangwen

AU - Li, Dali

AU - Wan, Ping

AU - Xia, Qiang

PY - 2025/4/11

Y1 - 2025/4/11

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105002778527

U2 - 10.1126/sciadv.adt9694

DO - 10.1126/sciadv.adt9694

M3 - 文章

C2 - 40203111

AN - SCOPUS:105002778527

SN - 2375-2548

VL - 11

JO - Science Advances

JF - Science Advances

IS - 15

M1 - eadt9694

ER -

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

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