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

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.