常见发育性癫痫性脑病遗传机制和靶向治疗前景

Genetic mechanisms and targeted treatment prospects for common developmental and epileptic encephalopathy

大多数发育性癫痫性脑病(developmental and epileptic encephalopathy,DEE)患者有遗传病因,如SCN1A、KCNQ2/KCNQ3、CDKL5和PCDH19等基因发生致病突变,患者同时存在认知功能障碍和严重的癫痫发作。虽然通过控制癫痫发作不能改善认知功能障碍,但是靶向治疗在个体化因素的背景下,可纠正DEE患者中具有明确分子遗传机制的病理生理过程,可以获得良好的临床预后。基于上述基因致病突变,反义寡核苷酸(antisense oligonucleotides,ASOs)、Ataluren、腺相关病毒载体和基因编辑等基因治疗可能是针对DEE有希望的靶向治疗策略,其中ASOs显示出治疗DEE的巨大潜力。下一代测序技术、动物模型、诱导多能干细胞技术、来自患者细胞的类器官和基因编辑技术可能会促进未来DEE靶向治疗的发展。

The majority of patients with developmental and epileptic encephalopathy(DEE)has genetic causes and presents with cognitive impairment and severe seizures.Although controlling seizures cannot improve cognitive impairment,targeted therapy based on individualized factors,corrects pathological and physiological processes with clear molecular genetic mechanisms in DEE patients,thereby achieving good clinical outcomes.According to the study of the molecular genetic mechanisms of related DEE such as SCN1A,KCNQ2/KCNQ3,CDKL5 and PCDH19,gene therapy such as antisense oligonucleotides(ASOs),Ataluren,adenovirus vectors,and gene editing has shown great promise for treatment of DEE,among which ASOs demonstrate enormous potential for treatment of DEE.Next-generation sequencing technologies,animal models,inducing polyenergic stem cell technologies,organ clusters from patient cells,and gene editing technologies can promote the development of future targeted epilepsy therapies.