基于Dystrophin治疗杜氏肌营养不良症的研究进展

Advances in Dystrophin-based Treatment of Duchenne Muscular Dystrophy

杜氏肌营养不良症(Duchenne muscular dystrophy,DMD)是一种严重进行性遗传性肌肉疾病,由X连锁阴性遗传,男性多见且多在儿童期即发病,不良结局包括心肌病甚至死亡,严重危害了全球儿童群体的身心健康。该疾病由抗肌萎缩蛋白基因(Dystrophin)基因突变导致,其编码的Dystrophin蛋白出现异常,Dystrophin蛋白位于肌细胞膜的内侧面,有四个主要的结构域:肌动蛋白结合氨基末端结构域(ABD1)、中心杆结构域、富含半胱氨酸的结构域和羧基末端结构域。Dystrophin蛋白负责维持肌纤维的强度、柔韧性和稳定性,并影响病灶粘附张力,同时还充当分子减震器,保护心肌细胞,使质膜免受损伤等。更多其他作用通常是根据它们所组成的复合物来考虑,包括在分化的肌肉细胞内外传递信号,以及控制活化的骨骼肌干(卫星)细胞的分裂动力学等,与身体各部位的调控紧密相关。该疾病属于罕见病,通过实验室检查、肌电图检查、核磁共振检查、基因检测、肌肉活检等进行及早诊断非常必要,以及时进行干预治疗和严格护理。但目前尚无根治方式,主要手段在于恢复Dystrophin蛋白以保持正常肌肉功能,包括:使用通读疗法、外显子跳跃疗法、病毒载体介导的基因疗法以及CRISPR/Cas9基因编辑疗法等;另有通过调控Dystrophin蛋白的相似蛋白Utrophin以期达到替代效果。文章通过查阅国内外相关文献对杜氏肌营养不良症的诊断、相关Dystrophin蛋白结构、功能、肌肉关系以及治疗进展作一综述。

Duchenne muscular dystrophy(DMD)is a severe progressive hereditary muscle disease,inherited by X-linked negative inheritance,with a male predominance and onset in childhood,and with adverse outcomes including cardiomyopathy and even death,which is a serious threat to the physical and mental health of the global pediatric population.The disease is caused by mutations in the dystrophin gene(dystrophin,DMD),which encodes an abnormal dystrophin protein.The dystrophin protein is located on the inner side of the myocyte membrane,and has four main structural domains:The actin-binding amino-terminal structural domain(ABD1),the central rod structural domain,the cysteine-rich structural domain,and the carboxylate terminal structural domain.The functional side is responsible for maintaining the strength,flexibility and stability of muscle fibers and influencing focal adhesion ten-sion,as well as acting as molecular shock absorbers,protecting cardiac myocytes from plasma membrane damage.More other roles are usually considered in the light of the complexes of which they are a part,including transmitting signals inside and outside of differen-tiated muscle cells and controlling the division kinetics of activated skeletal muscle stem(satellite)cells,etc.It is closely related to the regulation of various parts of the body.The disease is a rare condition and is characterized by laboratory tests,electromyography,MRI genetic testing,muscle biopsy,etc,early diagnosis is very essential for timely intervention treatment and strict care.However,there is currently no cure,and the main therapy is to restore the dystrophin protein to restore normal muscle function,including:The use of read-through therapies,exon jumping therapies,viral vector-mediated gene therapies,and CRISPR/Cas9 gene editing thera-pies,etc;and there are also some methods through regulating the dystrophin protein's analogous protein—utrophin,to achieve the substitution effect.In this article,the authors reviewed the diagnosis of Duchenne muscular dystrophy,the structure,function and muscle relationship of dystrophin proteins,as well as the therapeutic advances through the review of relevant literature at home and abroad.