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^*

^*Corresponding author for this work

School of Life Sciences

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English
Article number	eadt9694
Journal	Science Advances
Volume	11
Issue number	15
DOIs	https://doi.org/10.1126/sciadv.adt9694
State	Published - 11 Apr 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), Article 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",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "15",

}

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, vol. 11, no. 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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