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Updated: Aug 2, 2025
DNA Transfection of Mammalian Skeletal Muscles using In Vivo Electroporation
Published on: October 19, 2009
Enveloped viruses pseudotyped with mammalian myogenic cell fusogens target skeletal muscle for gene delivery
Sajedah M Hindi1, Michael J Petrany1, Elena Greenfeld2
1Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Abstract:
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.
Insights
Muscle fusion proteins Myomaker and Myomerger can be engineered onto enveloped viruses to specifically target skeletal muscle cells for gene therapy, offering a new delivery platform.
Area of Science:
- Biochemistry
- Cell Biology
- Virology
Background:
- Viral entry into cells relies on fusogenic proteins that mediate membrane fusion.
- Skeletal muscle development involves cell fusion mediated by muscle-specific fusogens, Myomaker and Myomerger.
- These muscle fusogens differ structurally and functionally from viral fusogens.
Purpose of the Study:
- To investigate if muscle fusogens can functionally replace viral fusogens for virus-cell fusion.
- To engineer enveloped viruses with muscle fusogens for targeted skeletal muscle transduction.
- To establish a novel platform for skeletal muscle gene delivery.
Main Methods:
- Engineering Myomaker and Myomerger onto the membrane of enveloped viruses.
- Assessing viral transduction specificity in skeletal muscle.
- Evaluating the therapeutic delivery of μDystrophin in a mouse model of Duchenne muscular dystrophy.
Main Results:
- Engineered viruses demonstrated specific transduction of skeletal muscle cells.
- Virions pseudotyped with muscle fusogens successfully delivered μDystrophin.
- Therapeutic delivery alleviated pathology in a Duchenne muscular dystrophy mouse model.
Conclusions:
- Muscle fusogens can be functionally adapted to mediate viral entry into skeletal muscle.
- This approach establishes a promising platform for targeted gene therapy in skeletal muscle disorders.
- Harnessing myogenic membrane properties offers a novel strategy for therapeutic material delivery.
