journal article·2026-01Open access

Treatment with Minicircle DNA Expressing a FGF23 Fragment in a Clinically relevant Mouse Model of X‐Linked Hypophosphatemic Rickets

Huixiao Wu, Wanyi Zhao, Xinyu Chen, Yanzhou Wang, Shuoshuo Wei, Bo Xiang, Yingzhou Shi, Zongyue Li, Yangyang Yao, Jin Xie, Renyuan Qiu, Meng Shu, Shuo Xu, Ping Chen, Zhiying Chen, Yingjie Wu, Weibo Xia, Ling Gao, Yongfeng Song, Jiajun Zhao, Chao Xu

Advanced Science· Volume 13· Issue 4

Abstract

Abstract X‐linked hypophosphatemic rickets (XLHR) is a rare X‐linked dominant skeletal dysplasia caused by phosphate regulating endopeptidase homolog X‐linked (PHEX) gene mutation. Until now, the pathogenic role of PHEX has not been fully determined, and there has been no radical cure for XLHR. In the previous study, a novel PHEX variant (c.T1349C; p.L450P) is identified in a child with XLHR. The present study aims to reveal its pathogenic role and evaluate the therapeutic effects of the minicircle (MC)‐DNA in XLHR. In vitro, the wildtype and mutant plasmids are introduced into HEK293 cells. In vivo, a new knock‐in XLHR mouse model carrying the novel variant is established. Furthermore, this study makes the first attempt to perform gene therapy using a MC‐DNA vector expressing a fragment of FGF23 (amino acids 180‐251) in the Phex ‐T1349C mice. The new mouse model demonstrates the clinical manifestations of XLHR seen in the patient, including a gene dosage effect. Furthermore, MC‐DNA is found to slightly increase blood phosphorus levels, significantly decrease serum alkaline phosphatase levels, and improve bone mineralization without apparent adverse effects for at least 6 weeks. This study suggests MC‐DNA as a promisingly safe and effective therapeutic strategy to treat XLHR.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Parathyroid Disorders and Treatments · Alkaline Phosphatase Research Studies · Heterotopic Ossification and Related Conditions

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology and Metabolism Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan 250021 P. R. China

Shandong Provincial Research Center for Stem Cells and Gene Therapy of Endocrine Metabolic Diseases Jinan 250021 P. R. China

Institute of Endocrinology Shandong Academy of Clinical Medicine Jinan 250021 P. R. China

Shandong Clinical Medical Center of Endocrinology and Metabolism Jinan 250021 P. R. China

Department of Pediatric Orthopedics Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan 250021 P. R. China

Department of Radiology Shandong Rongjun General Hospital Jinan 250013 P. R. China

Department of Medical imaging Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan 250021 P. R. China

Syno Minicircle Biotechnology Co. Ltd. Shenzhen 518107 P. R. China

College of Laboratory Animals (Shandong Laboratory Animal Center) Medical Science and Technology Innovation Center Shandong Provincial Hospital Shandong First Medical University & Shandong Academy of Medical Sciences Jinan 250117 P. R. China

Department of Endocrinology Peking Union Medical College Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100730 P. R. China

Funding

National Natural Science Foundation of China · National Major Science and Technology Projects of China

References (59)

Show source-provided references
1. 10.1172/JCI11927610.1172/JCI119276 ↗
2. 10.1093/hmg/10.15.153910.1093/hmg/10.15.1539 ↗
3. 10.1210/jc.2002-02180910.1210/jc.2002-021809 ↗
4. 10.1302/2046-3758.88.BJR-2018-0276.R110.1302/2046-3758.88.BJR-2018-0276.R1 ↗
5. 10.1038/s41581-022-00665-x10.1038/s41581-022-00665-x ↗
6. 10.1007/s11914-021-00709-410.1007/s11914-021-00709-4 ↗
7. 10.1186/s13023-019-1014-810.1186/s13023-019-1014-8 ↗
8. 10.1359/JBMR.030126410.1359/JBMR.0301264 ↗
9. 10.1002/jbmr.34010.1002/jbmr.340 ↗
10. 10.1111/bcp.1376310.1111/bcp.13763 ↗
11. 10.1056/NEJMoa171464110.1056/NEJMoa1714641 ↗
12. 10.1016/S0140-6736(19)31054-210.1016/S0140-6736(19)31054-2 ↗
13. 10.1016/S0140-6736(19)30654-310.1016/S0140-6736(19)30654-3 ↗
14. 10.1002/jbmr.347510.1002/jbmr.3475 ↗
15. 10.1210/clinem/dgac29610.1210/clinem/dgac296 ↗
16. 10.1016/S2213-8587(18)30338-310.1016/S2213-8587(18)30338-3 ↗
17. 10.1056/NEJMra170691010.1056/NEJMra1706910 ↗
18. 10.1056/NEJMc181577610.1056/NEJMc1815776 ↗
19. 10.1038/s41573-019-0012-910.1038/s41573-019-0012-9 ↗
20. 10.1007/s40259-017-0234-510.1007/s40259-017-0234-5 ↗
21. 10.1126/sciadv.abj501810.1126/sciadv.abj5018 ↗
22. 10.3389/fimmu.2021.82238910.3389/fimmu.2021.822389 ↗
23. 10.3389/fimmu.2021.65839910.3389/fimmu.2021.658399 ↗
24. 10.1089/hum.2020.31010.1089/hum.2020.310 ↗
25. 10.1208/s12248-021-00608-710.1208/s12248-021-00608-7 ↗
26. 10.1038/mtm.2014.6210.1038/mtm.2014.62 ↗
27. 10.1038/nmeth.142610.1038/nmeth.1426 ↗
28. 10.1038/nbt.170810.1038/nbt.1708 ↗
29. 10.1038/mt.2010.24910.1038/mt.2010.249 ↗
30. 10.1016/j.biomaterials.2020.12007210.1016/j.biomaterials.2020.120072 ↗
31. 10.1038/gt.2016.3710.1038/gt.2016.37 ↗
32. 10.1089/hum.2019.01410.1089/hum.2019.014 ↗
33. 10.1089/hum.2016.12210.1089/hum.2016.122 ↗
34. 10.1002/hep.2710410.1002/hep.27104 ↗
35. 10.1210/clinem/dgae12010.1210/clinem/dgae120 ↗
36. 10.1073/pnas.090200610710.1073/pnas.0902006107 ↗
37. 10.1093/hmg/6.2.16510.1093/hmg/6.2.165 ↗
38. 10.1016/S0002-9440(10)64468-910.1016/S0002-9440(10)64468-9 ↗
39. 10.1007/s00335-003-2310-z10.1007/s00335-003-2310-z ↗
40. 10.1007/s11373-007-9199-610.1007/s11373-007-9199-6 ↗
41. 10.1186/1423-0127-18-6010.1186/1423-0127-18-60 ↗
42. 10.1002/jcb.2411510.1002/jcb.24115 ↗
43. 10.1172/JCI11459010.1172/JCI114590 ↗
44. 10.1359/jbmr.08041710.1359/jbmr.080417 ↗
45. 10.1016/j.bone.2007.01.01710.1016/j.bone.2007.01.017 ↗
46. Ben‐Dov I. Z. · J. Clin. Invest. · 2007 · 117 · 4003
47. 10.1210/en.2003-176810.1210/en.2003-1768 ↗
48. 10.1016/j.bone.2012.05.01510.1016/j.bone.2012.05.015 ↗
49. 10.1172/JCI8192810.1172/JCI81928 ↗
50. 10.1038/gt.2008.18310.1038/gt.2008.183 ↗
51. 10.1007/s00223990023010.1007/s002239900230 ↗
52. 10.1016/S0092-8674(01)00622-510.1016/S0092-8674(01)00622-5 ↗
53. 10.1016/j.bone.2012.11.00710.1016/j.bone.2012.11.007 ↗
54. 10.1074/jbc.M80177420010.1074/jbc.M801774200 ↗
55. 10.1073/pnas.95.7.359710.1073/pnas.95.7.3597 ↗
56. 10.1530/JOE-12-014310.1530/JOE-12-0143 ↗
57. Li H. · Zhonghua Erke Zazhi · 2009 · 47 · 487
58. 10.1042/bj355070710.1042/bj3550707 ↗
59. 10.1016/j.omto.2022.02.01410.1016/j.omto.2022.02.014 ↗