Apert syndrome (AS), the most severe form of craniosynostosis, is caused by missense mutations including Pro253Arg(P253R) of fibroblast growth factor receptor 2 (FGFR2), which leads to enhanced FGF/FGFR2-signaling activity. Surgical correction of the deformed skull is the typical treatment for AS. Because of constant maldevelopment of sutures, the corrective surgery is often executed several times, resulting in increased patient challenge and complications. Biological therapies targeting the signaling of mutant FGFR2 allele, in combination with surgery, may bring better outcome. Here we screened and found a small interfering RNA (siRNA) specifically targeting the Fgfr2-P253R allele, and we revealed that it inhibited osteoblastic differentiation and matrix mineralization by reducing the signaling of ERK1/2 and P38 in cultured primary calvarial cells and calvarial explants from Apert mice (Fgfr2^+/P253R). Furthermore, AAV9 carrying short hairpin RNA (shRNA) (AAV9-Fgfr2-shRNA) against mutant Fgfr2 was delivered to the skulls of AS mice. Results demonstrate that AAV9-Fgfr2-shRNA attenuated the premature closure of coronal suture and the decreased calvarial bone volume of AS mice. Our study provides a novel practical biological approach, which will, in combination with other therapies, including surgeries, help treat patients with AS while providing experimental clues for the biological therapies of other genetic skeletal diseases.

Apert综合征（AS）是颅骨融合的最严重形式，是由错义突变（包括成纤维细胞生长因子受体2（FGFR2）的Pro253Arg（P253R））引起的，该突变导致FGF / FGFR2信号转导活性增强。畸形颅骨的手术矫正是AS的典型治疗方法。由于缝线不断地发展不良，矫正手术通常执行几次，导致患者的挑战和并发症增加。针对突变FGFR2等位基因信号转导的生物疗法，与手术相结合，可能会带来更好的结果。在这里我们筛选并发现了一个专门针对Fgfr2-P253R的小干扰RNA（siRNA）等位基因，我们发现它通过减少培养的原发性颅盖膜细胞和来自Apert小鼠的颅盖膜外植体（Fgfr2 ^{+ / P253R}）中ERK1 / 2和P38的信号传导来抑制成骨细胞分化和基质矿化。此外，携带针对突变体Fgfr2的短发夹RNA（shRNA）（AAV9 - Fgfr2- shRNA）的AAV9被递送至AS小鼠的头骨。结果表明，AAV9- Fgfr2-shRNA减弱了AS小鼠的冠状缝线过早闭合和颅骨骨量减少。我们的研究提供了一种新颖的实用生物学方法，它将与包括外科手术在内的其他疗法结合，帮助治疗AS患者，同时为其他遗传骨骼疾病的生物学疗法提供实验线索。