Atavistic strategy for the treatment of hyperuricemia via ionizable liposomal mRNA

Mengjie Zhang, Abid Hussain, Bo Hu, Haiyin Yang, Chunhui Li, Shuai Guo, Xiaofeng Han, Bei Li, Yunlu Dai, Yuhong Cao, Hang Chi, Yuhua Weng, Cheng-Feng Qin and Yuanyu Huang ()
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Mengjie Zhang: Beijing Institute of Technology
Abid Hussain: Beijing Institute of Technology
Bo Hu: Beijing Institute of Technology
Haiyin Yang: Beijing Institute of Technology
Chunhui Li: Beijing Institute of Technology
Shuai Guo: Beijing Institute of Technology
Xiaofeng Han: Beijing Institute of Technology
Bei Li: University of Macau
Yunlu Dai: University of Macau
Yuhong Cao: National Center for Nanoscience and Technology, Chinese Academy of Sciences
Hang Chi: Beijing Institute of Microbiology and Epidemiology
Yuhua Weng: Beijing Institute of Technology
Cheng-Feng Qin: Beijing Institute of Microbiology and Epidemiology
Yuanyu Huang: Beijing Institute of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Hyperuricemia is associated with an increased risk of gout, hypertension, diabetes, and cardiovascular diseases. Most mammals maintain normal serum uric acid (SUA) via urate oxidase (Uox), an enzyme that metabolizes poorly-soluble UA to highly-soluble allantoin. In contrast, Uox became a pseudogene in humans and apes over the long course of evolution. Here we demonstrate an atavistic strategy for treating hyperuricemia based on endogenous expression of Uox in hepatocytes mediated by mRNA (mUox) loaded with an ionizable lipid nanoparticle termed iLAND. mUox@iLAND allows effective transfection and protein expression in vitro. A single dose of mUox@iLAND lowers SUA levels for several weeks in two female murine models, including a novel long-lasting model, which is also confirmed by metabolomics analysis. Together with the excellent safety profiles observed in vivo, the proposed mRNA agent demonstrates substantial potential for hyperuricemia therapy and the prevention of associated conditions.

Date: 2024
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DOI: 10.1038/s41467-024-50752-9

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