Preclinical evaluation of AGT mRNA replacement therapy for primary hyperoxaluria type I disease
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 <i>AGT</i> mRNA (<i>hAGT</i> 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 <i>AGT</i> mRNA and AGT protein maintained high expression levels for up to 48 hours. A single 2 mg/kg dose in <i>Agxt</i>Q84<sup>-/-</sup> 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 <i>hAGT</i> mRNA/LPP and support its clinical application in PH1 treatment.
Authors
- Amar Deep Sharma
- Michael Ott
- Xiaochen Bo (ORCID: https://orcid.org/0000-0003-1911-7922)
- Hangwen Li
- Jie Zhao (ORCID: https://orcid.org/0000-0002-3209-3534)
- D. Zhang (ORCID: https://orcid.org/0009-0006-4623-0153)
- Dali Li (ORCID: https://orcid.org/0000-0002-0046-8493)
- Qiang Xia (ORCID: https://orcid.org/0000-0001-9482-6951)
- Haifa Shen (ORCID: https://orcid.org/0000-0002-9728-5430)
- Xinye Zhu (ORCID: https://orcid.org/0000-0001-7332-1903)
- Liang Zhang (ORCID: https://orcid.org/0000-0003-1146-7848)
- Jie Li (ORCID: https://orcid.org/0009-0006-8674-1775)
- Ping Wan (ORCID: https://orcid.org/0000-0003-2884-6270)
- Hongquan Geng (ORCID: https://orcid.org/0000-0003-4722-416X)
- Qinggong Yuan (ORCID: https://orcid.org/0000-0001-8446-8193)
- Yiqing Zhang (ORCID: https://orcid.org/0000-0003-4434-6890)
- Yiyangzi Ma (ORCID: https://orcid.org/0000-0002-9681-9162)
- Taihua Yang (ORCID: https://orcid.org/0000-0001-6767-5027)
- Siyuan Tang (ORCID: https://orcid.org/0000-0002-4905-8428)
- Mei Long
- Jiahao Ge (ORCID: https://orcid.org/0009-0005-2074-2719)
- Yicheng Zhao
- Lei Huang (ORCID: https://orcid.org/0000-0001-6847-6302)
Institutions
- Shanghai Jiao Tong University (CN)
- Jilin University (CN)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- Renji Hospital (CN)
- XinHua Hospital (CN)
- Medizinische Hochschule Hannover (DE)
- Shanghai Institute of Organic Chemistry (CN)
- Mirna Therapeutics (United States) (US)
- Children's Hospital of Fudan University (CN)
- Organ Transplantation and Immunology Institute (IT)
- East China Normal University (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2025-04-09
- DOI
- https://doi.org/10.1126/sciadv.adt9694
- Citations
- 10
- Primary Topic
- Kidney Stones and Urolithiasis Treatments
- Type
- article
- Field-Weighted Citation Impact
- 15.18