Enveloped viruses pseudotyped with mammalian myogenic cell fusogens target skeletal muscle for gene delivery

• DOI: 10.1016/j.cell.2023.03.033
• Publication Date: 2023-04-18T14:29:20Z
• Authors: Sajedah M. Hindi; Michael J. Petrany; Elena Greenfeld; Leah C. Focke; Alyssa A.W. Cramer; Michael A. Whitt; Ramzi J. Khairallah; Christopher W. Ward; Jeffrey S. Chambe...; Vikram Prasad; Benjamin Podbilewicz; Douglas P. Millay
• Keywords: Cell Fusion; Muscular Dystrophy, Duchenne; Mice; Disease Models, Animal; Viral Tropism; Lentivirus; Animals; Membrane Proteins; Bioengineering; Muscle Development; Muscle, Skeletal; Membrane Fusion; 3. Good health

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.