The microcephaly-capillary malformation (MIC-CAP) syndrome is a life-threatening disease caused by biallelic mutations of the STAMBP gene, which encodes an endosomal deubiquitinating enzyme. To establish a suitable preclinical animal model for clinical therapeutic practice, we generated a central nervous system (CNS)-specific Stambp knockout mouse model (Stambp Sox1−cKO) that phenocopies Stambp null mice including progressive microcephaly, postnatal growth retardation and complete penetrance of preweaning death. In this MIC-CAP syndrome mouse model, early-onset neuronal death occurs specifically in the hippocampus and cortex, accompanied by aggregation of ubiquitinated proteins, and massive neuroinflammation. Importantly, neonatal AAV9-mediated gene supplementation of Stambp in the brain could significantly improve neurological defects, sustain growth, and prolong the lifespan of StambpSox1−cKO mice. Together, our findings reveal a central role of brain defects in the pathogenesis of STAMBP deficiency and provide preclinical evidence that postnatal gene replacement is an effective approach to cure the disease.

中文翻译：

---

AAV 介导的 Stambp 基因替代疗法挽救了小头畸形-毛细血管畸形综合征小鼠模型中的神经缺陷


小头畸形-毛细血管畸形 （MIC-CAP） 综合征是一种危及生命的疾病，由 STAMBP 基因的双等位基因突变引起，STAMBP 基因编码一种内体去泛素化酶。为了建立适合临床治疗实践的临床前动物模型，我们生成了中枢神经系统 （CNS） 特异性 Stambp 敲除小鼠模型 （StambpSox1-cKO），该模型对 Stambp 缺失小鼠进行表型复制，包括进行性小头畸形、出生后生长迟缓和断奶前死亡的完全外显。在这种 MIC-CAP 综合征小鼠模型中，早发性神经元死亡特别发生在海马体和皮层，伴有泛素化蛋白的聚集和大规模的神经炎症。重要的是，新生 AAV9 介导的大脑中 Stambp 基因补充可以显着改善神经系统缺陷，维持生长，并延长 StambpSox1−cKO 小鼠的寿命。总之，我们的研究结果揭示了大脑缺陷在 STAMBP 缺陷发病机制中的核心作用，并提供了临床前证据，证明出生后基因替代是治愈该疾病的有效方法。