Swearson Samuel, Eliason Steve, Su Dan, Rice Kevin G, Amendt Brad A
Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Craniofacial Anomalies Research Center, University of Iowa, Iowa City, IA, 52242.
Sci Adv. 2025 Aug 22;11(34):eadx9763. doi: 10.1126/sciadv.adx9763.
Craniosynostosis is a common birth defect affecting 1 of the 2200 live births causing severe skull and cognitive defects, due to premature cranial suture fusion. The current surgical treatments require invasive calvaria vault remodeling and cranial bone resection in the baby. We demonstrate that inhibition of in mice results in coronal suture fusion (craniosynostosis). Therefore, we use overexpression of to prevent suture fusion in mutant mice, a well-known model for craniosynostosis. We developed a PEGylated-peptide nanoparticle system to deliver plasmid DNA expressing directly to the sutures of postnatal day 4 (P4) mutant mice before suture fusion. Injection of the nanoparticles under the scalp before suture fusion at P7 to P10 inhibited suture fusion. Treatments increased Gli1- and Six2-positive suture stem cells and the thickness of the periosteum layer. The treated mice increased body weight and were alert and active. We demonstrate an effective noninvasive gene therapy treatment for craniosynostosis.
颅缝早闭是一种常见的出生缺陷，每2200例活产中就有1例受其影响，由于颅骨缝线过早融合，会导致严重的颅骨和认知缺陷。目前的手术治疗需要对婴儿进行侵入性的颅盖重塑和颅骨切除。我们证明，在小鼠中抑制 会导致冠状缝融合（颅缝早闭）。因此，我们利用 的过表达来防止颅缝早闭的著名模型—— 突变小鼠的缝线融合。我们开发了一种聚乙二醇化肽纳米颗粒系统，在出生后第4天（P4）的 突变小鼠缝线融合前将表达 的质粒DNA直接递送至缝线处。在P7至P10缝线融合前将 纳米颗粒注射到头皮下可抑制缝线融合。治疗增加了Gli1和Six2阳性的缝线干细胞以及骨膜层的厚度。接受治疗的 小鼠体重增加，警觉且活跃。我们证明了一种针对颅缝早闭的有效非侵入性基因治疗方法。
