Hindi Sajedah M, Petrany Michael J, Greenfeld Elena, Focke Leah C, Cramer Alyssa A W, Whitt Michael A, Prasad Vikram, Chamberlain Jeffrey S, Podbilewicz Benjamin, Millay Douglas P
Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
bioRxiv. 2023 Mar 18:2023.03.17.533157. doi: 10.1101/2023.03.17.533157.
Entry of enveloped viruses into cells is mediated by fusogenic proteins that form a complex between membranes to drive rearrangements needed for fusion. 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 if 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 micro-Dystrophin (μDys) to skeletal muscle of a mouse model of Duchenne muscular dystrophy. Through harnessing the intrinsic properties of myogenic membranes, we establish a platform for delivery of therapeutic material to skeletal muscle.
包膜病毒进入细胞是由融合蛋白介导的，这些融合蛋白在膜之间形成复合物，以驱动融合所需的重排。骨骼肌发育也需要祖细胞之间的膜融合事件来形成多核肌纤维。肌生成素和肌融合素是肌肉特异性细胞融合蛋白，但在结构和功能上与经典病毒融合蛋白不同。我们想知道，尽管肌肉融合蛋白在结构上有独特性，但它们是否能在功能上替代病毒融合蛋白，使病毒与细胞融合。我们报告称，在包膜病毒膜上设计肌生成素和肌融合素可导致骨骼肌的特异性转导。我们还证明，用肌肉融合蛋白假型化的局部和全身注射的病毒粒子可以将微型抗肌萎缩蛋白（μDys）递送至杜兴氏肌营养不良小鼠模型的骨骼肌。通过利用成肌膜的内在特性，我们建立了一个向骨骼肌递送治疗物质的平台。
