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Apert syndrome (AS) is characterized by synostosis of coronal sutures, midfacial hypoplasia,abnormity of brain, syndactyly of hands and feet. Majority of AS is caused by gain-of-function mutation of fibro‐blast growth factor receptor 2 (FGFR2). To date, the treatment of AS is surgical correction for the deformed skull.The reconstruction of sutures is often executed several times, because of constant premature of sutures. Some dis‐eased tissues, such as brain, are difficult to treat with surgery. CRISPR/Cas9 gene editing technology exhibits pow‐erful prospect in the treatment of human genetic diseases. In this study, small guiding RNA (gRNA) specificallytargeting the Fgfr2 gene was screened and lentivirus mediated Cas9/gRNA was employed to treat mice (Fg‐fr2+/P253R) that mimicking human Apert syndrome in primary calvarial cells, calvarial explants or calvarial bone. Incultured primary calvarial cells, Cas9/gRNA reduced the phosphorylation of ERK1/2 and P38, and resultantly inhibited osteoblastic differentiation and matrix mineralization. Besides, Cas9/gRNA attenuated the premature closure ofcoronal suture and the decreased calvarial bone volume calvarial explants and AS mice. This study provides exper‐imental basis of gene therapy for Apert syndrome, and is prospective to provide new strategies for the treatment ofskeletal genetic diseases.