Division of Molecular and Medical Genetics, Center for Gene and Cell Therapy, The Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan.
Int J Mol Sci. 2022 Jan 28;23(3):1551. doi: 10.3390/ijms23031551.
Duchenne muscular dystrophy (DMD) is caused by loss-of-function mutations in the dystrophin gene on chromosome Xp21. Disruption of the dystrophin-glycoprotein complex (DGC) on the cell membrane causes cytosolic Ca influx, resulting in protease activation, mitochondrial dysfunction, and progressive myofiber degeneration, leading to muscle wasting and fragility. In addition to the function of dystrophin in the structural integrity of myofibers, a novel function of asymmetric cell division in muscular stem cells (satellite cells) has been reported. Therefore, it has been suggested that myofiber instability may not be the only cause of dystrophic degeneration, but rather that the phenotype might be caused by multiple factors, including stem cell and myofiber functions. Furthermore, it has been focused functional regulation of satellite cells by intracellular communication of extracellular vesicles (EVs) in DMD pathology. Recently, a novel molecular mechanism of DMD pathogenesis-circulating RNA molecules-has been revealed through the study of target pathways modulated by the Neutral sphingomyelinase2/Neutral sphingomyelinase3 () protein. In addition, adeno-associated virus (AAV) has been clinically applied for DMD therapy owing to the safety and long-term expression of transduction genes. Furthermore, the EV-capsulated AAV vector (EV-AAV) has been shown to be a useful tool for the intervention of DMD, because of the high efficacy of the transgene and avoidance of neutralizing antibodies. Thus, we review application of AAV and EV-AAV vectors for DMD as novel therapeutic strategy.
杜氏肌营养不良症（DMD）是由 Xp21 染色体上的肌营养不良蛋白基因突变引起的。细胞膜上的肌营养不良蛋白糖蛋白复合物（DGC）的破坏导致细胞质内 Ca2+内流，进而导致蛋白酶激活、线粒体功能障碍和进行性肌纤维变性，导致肌肉萎缩和脆弱。除了肌营养不良蛋白在肌纤维结构完整性中的功能外，肌肉干细胞（卫星细胞）的不对称细胞分裂的新功能也有报道。因此，有人认为肌纤维不稳定可能不是进行性肌营养不良变性的唯一原因，而是表型可能由多种因素引起，包括干细胞和肌纤维功能。此外，细胞外囊泡（EVs）的细胞内通讯对卫星细胞的功能调节作用在 DMD 病理中受到关注。最近，通过研究受中性鞘磷脂酶 2/中性鞘磷脂酶 3（）蛋白调节的靶向途径，揭示了 DMD 发病机制的一种新的分子机制——循环 RNA 分子。此外，由于转导基因的安全性和长期表达，腺相关病毒（AAV）已在临床上应用于 DMD 治疗。此外，由于转基因的高效性和避免中和抗体，EV 包裹的 AAV 载体（EV-AAV）已被证明是干预 DMD 的有用工具。因此，我们综述了 AAV 和 EV-AAV 载体在 DMD 作为新型治疗策略中的应用。
