Mao Yilin, Evans Elizabeth E, Mishra Vikas, Balch Leslie, Eberhardt Allison, Zauderer Maurice, Gold Wendy A
Molecular Neurobiology Research Laboratory, Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia.
Int J Mol Sci. 2021 Aug 31;22(17):9465. doi: 10.3390/ijms22179465.
Rett syndrome is a neurodevelopmental disorder caused by mutations of the methyl-CpG binding protein 2 gene. Abnormal physiological functions of glial cells contribute to pathogenesis of Rett syndrome. Semaphorin 4D (SEMA4D) regulates processes central to neuroinflammation and neurodegeneration including cytoskeletal structures required for process extension, communication, and migration of glial cells. Blocking SEMA4D-induced gliosis may preserve normal glial and neuronal function and rescue neurological dysfunction in Rett syndrome. We evaluated the pre-clinical therapeutic efficacy of an anti-SEMA4D monoclonal antibody in the Rett syndrome Mecp2T158A transgenic mouse model and investigated the contribution of glial cells as a proposed mechanism of action in treated mice and in primary glial cultures isolated from Mecp2T158A/y mutant mice. SEMA4D is upregulated in neurons while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1-positive cells are upregulated in Mecp2T158A/y mice. Anti-SEMA4D treatment ameliorates Rett syndrome-specific symptoms and improves behavioural functions in both pre-symptomatic and symptomatic cohorts of hemizygous Mecp2T158A/y male mice. Anti-SEMA4D also reduces astrocyte and microglia activation in vivo. In vitro experiments demonstrate an abnormal cytoskeletal structure in mutant astrocytes in the presence of SEMA4D, while anti-SEMA4D antibody treatment blocks SEMA4D-Plexin B1 signaling and mitigates these abnormalities. These results suggest that anti-SEMA4D immunotherapy may be an effective treatment option to alleviate symptoms and improve cognitive and motor function in Rett syndrome.
瑞特综合征是一种由甲基-CpG结合蛋白2基因突变引起的神经发育障碍。胶质细胞的异常生理功能促成了瑞特综合征的发病机制。信号素4D（SEMA4D）调节神经炎症和神经退行性变的核心过程，包括胶质细胞突起延伸、通讯和迁移所需的细胞骨架结构。阻断SEMA4D诱导的胶质增生可能会保留正常的胶质和神经元功能，并挽救瑞特综合征中的神经功能障碍。我们评估了一种抗SEMA4D单克隆抗体在瑞特综合征Mecp2T158A转基因小鼠模型中的临床前治疗效果，并研究了胶质细胞在治疗小鼠和从Mecp2T158A/y突变小鼠分离的原代胶质细胞培养物中的作用机制。在Mecp2T158A/y小鼠中，神经元中的SEMA4D上调，而胶质纤维酸性蛋白和离子化钙结合衔接分子1阳性细胞上调。抗SEMA4D治疗可改善半合子Mecp2T158A/y雄性小鼠无症状和有症状队列中的瑞特综合征特异性症状，并改善行为功能。抗SEMA4D还可在体内减少星形胶质细胞和小胶质细胞的激活。体外实验表明，在存在SEMA4D的情况下，突变星形胶质细胞的细胞骨架结构异常，而抗SEMA4D抗体治疗可阻断SEMA4D-Plexin B1信号传导并减轻这些异常。这些结果表明，抗SEMA4D免疫疗法可能是缓解瑞特综合征症状并改善认知和运动功能的有效治疗选择。
