Uricase-Expressing Engineered Macrophages Alleviate Murine Hyperuricemia
<b>Background</b>: Uricase, or urate oxidase (Uox) is a key enzyme in uric acid (UA) metabolism and has been applied in clinical treatment of human hyperuricemia (HUA). However, the current clinically applied uricases, despite their potent urate-lowering capacity, tend to form anti-drug...
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2024-11-01
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| author | Yu-Zhong Feng Hao Cheng Guo-Qing Xiong Jia-Zhen Cui Zhi-Li Chen Yuan-Yuan Lu Zhi-Xin Meng Chen Zhu Hao-Long Dong Xiang-Hua Xiong Gang Liu Qing-Yang Wang Hui-Peng Chen |
| author_facet | Yu-Zhong Feng Hao Cheng Guo-Qing Xiong Jia-Zhen Cui Zhi-Li Chen Yuan-Yuan Lu Zhi-Xin Meng Chen Zhu Hao-Long Dong Xiang-Hua Xiong Gang Liu Qing-Yang Wang Hui-Peng Chen |
| author_sort | Yu-Zhong Feng |
| collection | DOAJ |
| description | <b>Background</b>: Uricase, or urate oxidase (Uox) is a key enzyme in uric acid (UA) metabolism and has been applied in clinical treatment of human hyperuricemia (HUA). However, the current clinically applied uricases, despite their potent urate-lowering capacity, tend to form anti-drug antibodies because of their immunogenicity, leading to increased risk of anaphylaxis, faster drug clearance and reduced or even complete loss of therapeutic effect, limiting their clinical application. In this study, we constructed engineered macrophages that stably expressed uricase, which might serve as a promising alternative to the direct injection of uricases. <b>Materials and Methods</b>: Engineered macrophages RAW264.7 cells were injected intravenously to treat hyperuricemic KM mice. Serum uric acid and bio-indicators for renal and hepatic functions were detected by an automatic biochemical analyzer; inflammatory cytokines were determined by ELISA; the livers and kidneys of the mice were sectioned for histological examination. <b>Results</b>: The uricase-expressing macrophages reduced UA levels from 300 ± 1.5 μmol/L to 101 ± 8.3 μmol/L in vitro. And in an HUA mouse model established by gavage with yeast extract, intravenous injection of the engineered macrophages could reduce the serum uric acid (sUA) of mice to normal level on the 14th day of modeling, with a decrease of 48.6%, and the urate-lowering effect was comparable to that of the first-line clinical drug allopurinol. In terms of safety, engineered macrophages did not cause liver or kidney dysfunction in mice, nor did they induce systemic immune response. <b>Conclusions</b>: Using macrophages as a chassis to deliver uricase might be a new, safe and effective strategy for the treatment and control of hyperuricemia. |
| format | Article |
| id | doaj-art-0af7a33bad0d416f9938b4d4f3715073 |
| institution | OA Journals |
| issn | 2227-9059 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-0af7a33bad0d416f9938b4d4f37150732025-08-20T02:28:02ZengMDPI AGBiomedicines2227-90592024-11-011211260210.3390/biomedicines12112602Uricase-Expressing Engineered Macrophages Alleviate Murine HyperuricemiaYu-Zhong Feng0Hao Cheng1Guo-Qing Xiong2Jia-Zhen Cui3Zhi-Li Chen4Yuan-Yuan Lu5Zhi-Xin Meng6Chen Zhu7Hao-Long Dong8Xiang-Hua Xiong9Gang Liu10Qing-Yang Wang11Hui-Peng Chen12Academy of Military Medical Sciences, Beijing 100071, ChinaAcademy of Military Medical Sciences, Beijing 100071, ChinaAcademy of Military Medical Sciences, Beijing 100071, ChinaAcademy of Military Medical Sciences, Beijing 100071, ChinaAcademy of Military Medical Sciences, Beijing 100071, ChinaInstitutes of Physical Science and Information Technology, Anhui University, Hefei 230000, ChinaSchool of Life Science, Hebei University, Baoding 071000, ChinaAcademy of Military Medical Sciences, Beijing 100071, ChinaAcademy of Military Medical Sciences, Beijing 100071, ChinaAcademy of Military Medical Sciences, Beijing 100071, ChinaAcademy of Military Medical Sciences, Beijing 100071, ChinaAcademy of Military Medical Sciences, Beijing 100071, ChinaAcademy of Military Medical Sciences, Beijing 100071, China<b>Background</b>: Uricase, or urate oxidase (Uox) is a key enzyme in uric acid (UA) metabolism and has been applied in clinical treatment of human hyperuricemia (HUA). However, the current clinically applied uricases, despite their potent urate-lowering capacity, tend to form anti-drug antibodies because of their immunogenicity, leading to increased risk of anaphylaxis, faster drug clearance and reduced or even complete loss of therapeutic effect, limiting their clinical application. In this study, we constructed engineered macrophages that stably expressed uricase, which might serve as a promising alternative to the direct injection of uricases. <b>Materials and Methods</b>: Engineered macrophages RAW264.7 cells were injected intravenously to treat hyperuricemic KM mice. Serum uric acid and bio-indicators for renal and hepatic functions were detected by an automatic biochemical analyzer; inflammatory cytokines were determined by ELISA; the livers and kidneys of the mice were sectioned for histological examination. <b>Results</b>: The uricase-expressing macrophages reduced UA levels from 300 ± 1.5 μmol/L to 101 ± 8.3 μmol/L in vitro. And in an HUA mouse model established by gavage with yeast extract, intravenous injection of the engineered macrophages could reduce the serum uric acid (sUA) of mice to normal level on the 14th day of modeling, with a decrease of 48.6%, and the urate-lowering effect was comparable to that of the first-line clinical drug allopurinol. In terms of safety, engineered macrophages did not cause liver or kidney dysfunction in mice, nor did they induce systemic immune response. <b>Conclusions</b>: Using macrophages as a chassis to deliver uricase might be a new, safe and effective strategy for the treatment and control of hyperuricemia.https://www.mdpi.com/2227-9059/12/11/2602uricasehyperuricemiamacrophage therapyengineered macrophages |
| spellingShingle | Yu-Zhong Feng Hao Cheng Guo-Qing Xiong Jia-Zhen Cui Zhi-Li Chen Yuan-Yuan Lu Zhi-Xin Meng Chen Zhu Hao-Long Dong Xiang-Hua Xiong Gang Liu Qing-Yang Wang Hui-Peng Chen Uricase-Expressing Engineered Macrophages Alleviate Murine Hyperuricemia Biomedicines uricase hyperuricemia macrophage therapy engineered macrophages |
| title | Uricase-Expressing Engineered Macrophages Alleviate Murine Hyperuricemia |
| title_full | Uricase-Expressing Engineered Macrophages Alleviate Murine Hyperuricemia |
| title_fullStr | Uricase-Expressing Engineered Macrophages Alleviate Murine Hyperuricemia |
| title_full_unstemmed | Uricase-Expressing Engineered Macrophages Alleviate Murine Hyperuricemia |
| title_short | Uricase-Expressing Engineered Macrophages Alleviate Murine Hyperuricemia |
| title_sort | uricase expressing engineered macrophages alleviate murine hyperuricemia |
| topic | uricase hyperuricemia macrophage therapy engineered macrophages |
| url | https://www.mdpi.com/2227-9059/12/11/2602 |
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