Development of a Mouse Model of Sturge-Weber Syndrome and Therapeutic Response to Imatinib. Development of a Mouse Model of Sturge-Weber Syndrome and Therapeutic Response to Imatinib

Sturge-Weber Syndrome (SWS) is a common vascular malformation caused by mutation of GNAQ in endothelial cells. No effective medical therapy exists for SWS, and therapy is mainly surgical. Progress in the medical treatment of SWS has been hindered by the lack of an animal model. We introduced mutant GNAQ into an immortalized murine endothelial cell line, MS1. The resultant cells form slow growing vascular malformations that morphologically and biochemically resemble human SWS. One of the genes upregulated as a result of mutant GNAQ is c-kit, which is a targetable event. Given that the FDA approved drug imatinib targets c-kit as well as its original target, bcr-abl, we evaluated the ability of imatinib to prevent the growth of vascular malformations in mice. We saw that imatinib significantly inhibits the growth of vascular malformations in vivo. Repurposing of imatinib for the treatment of SWS should be evaluated in a clinical trial. Overall design: ATAC-seq analysis.

斯特奇-韦伯综合征（SWS）是一类由内皮细胞GNAQ基因突变诱发的常见血管畸形。目前针对SWS尚无有效的内科治疗手段，临床治疗以手术为主。由于缺乏适配的动物模型，SWS的内科治疗研究进展长期受阻。我们将突变型GNAQ导入永生化小鼠内皮细胞系MS1中，获得的工程细胞可形成生长缓慢的血管畸形，其形态学与生化特征均与人类SWS病变高度相似。突变型GNAQ可上调多个基因的表达，其中c-kit即为可靶向干预的靶点之一。鉴于美国食品药品监督管理局（FDA）获批药物伊马替尼（imatinib）可同时靶向c-kit及其原始靶点bcr-abl，我们评估了伊马替尼对小鼠体内血管畸形生长的抑制效果。实验结果显示，伊马替尼可在体内显著抑制血管畸形的生长。因此，采用伊马替尼老药新用治疗SWS的方案，有待开展临床试验进一步验证。整体实验设计：ATAC-seq分析。