Enveloped viruses pseudotyped with mammalian myogenic cell fusogens target skeletal muscle for gene delivery.
Enveloped viruses pseudotyped with mammalian myogenic cell fusogens target skeletal muscle for gene delivery.
复制标题
用哺乳动物生肌细胞融合剂假型化的包膜病毒以骨骼肌为目标进行基因传递。
DOI：
10.1016/j.cell.2023.06.025
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发表时间：
2023
期刊：
影响因子：
64.5
通讯作者：
Millay,DouglasP
中科院分区：
文献类型：
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作者：
Hindi,SajedahM;Petrany,MichaelJ;Greenfeld,Elena;Focke,LeahC;Cramer,AlyssaAW;Whitt,MichaelA;Khairallah,RamziJ;Ward,ChristopherW;Chamberlain,JeffreyS;Prasad,Vikram;Podbilewicz,Benjamin;Millay,DouglasP
包膜病毒进入细胞由病毒融合蛋白介导，病毒融合蛋白驱动病毒和靶膜之间融合所需的膜重排。骨骼肌发育还需要祖细胞之间的膜融合事件以形成多核肌纤维。Myomaker和Myomerger是肌肉特异性细胞融合子，但在结构或功能上与经典病毒融合子不同。我们问肌肉融合因子是否可以在功能上替代病毒融合因子，尽管它们的结构独特，并融合病毒到细胞。我们报告，工程Myomaker和Myomerger的包膜病毒的膜上导致骨骼肌的特异性转导。我们还证明，局部和全身注射的病毒粒子假型与肌肉融合体可以提供μ肌营养不良蛋白的骨骼肌的杜氏肌营养不良症的小鼠模型和减轻病理。通过利用肌源性膜的内在特性，我们建立了一个平台，用于将治疗材料递送到骨骼肌。
Entry of enveloped viruses into cells is mediated by viral fusogenic proteins that drive membrane rearrangements needed for fusion between viral and target membranes. Skeletal muscle development also requires membrane fusion events between progenitor cells to form multinucleated myofibers. Myomaker and Myomerger are muscle-specific cell fusogens but do not structurally or functionally resemble classical viral fusogens. We asked whether the muscle fusogens could functionally substitute for viral fusogens, despite their structural distinctiveness, and fuse viruses to cells. We report that engineering of Myomaker and Myomerger on the membrane of enveloped viruses leads to specific transduction of skeletal muscle. We also demonstrate that locally and systemically injected virions pseudotyped with the muscle fusogens can deliver μDystrophin to skeletal muscle of a mouse model of Duchenne muscular dystrophy and alleviate pathology. Through harnessing the intrinsic properties of myogenic membranes, we establish a platform for delivery of therapeutic material to skeletal muscle.