Search

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. [Display omitted] • Skeletal muscle fusogens can replace viral fusogens and fuse viruses to cells • Lentiviruses pseudotyped with Mymk+Mymg specifically transduce skeletal muscle • Mymk+Mymg-lentiviral transduction requires Myomaker expression in recipient cells • Systemic administration of Mymk+Mymg-lentiviruses delivers therapeutic cargo By swapping viral fusogenic proteins (which help viruses fuse with and enter host cells) with mammalian skeletal muscle fusogenic proteins, it is possible to create viral vectors specifically targeted to skeletal muscle for gene therapy of Duchenne muscular dystrophy in mouse models. [ABSTRACT FROM AUTHOR]