6533b7ddfe1ef96bd12748d3
RESEARCH PRODUCT
Combined effect of AAV-U7-induced dystrophin exon skipping and soluble activin Type IIB receptor in mdx mice.
Willem M.h. HoogaarsArnaud FerryArnaud FerryElja SchirwisArja PasternackKarima RelizaniKarima RelizaniMarkus SchuelkeHelge AmthorHelge AmthorPeter A C 'T HoenJuha J. HulmiOlli RitvosEtienne MouiselLuis Garciasubject
musculoskeletal diseasesmdx mousemedicine.medical_specialtycongenital hereditary and neonatal diseases and abnormalitiesDuchenne muscular dystrophyActivin Receptors Type IIGenetic VectorsMyostatinBiologyDystrophin03 medical and health sciencesMice0302 clinical medicineInternal medicineGeneticsmedicineMyocyteAnimalsMuscular dystrophyMuscle SkeletalMolecular Biology030304 developmental biology0303 health sciencesBody WeightSkeletal muscleExonsGenetic TherapyDependovirusMuscular Dystrophy Animalmedicine.diseasemusculoskeletal system3. Good healthMice Inbred C57BLEndocrinologymedicine.anatomical_structureImmunologybiology.proteinMice Inbred mdxMolecular MedicineITGA7Dystrophin030217 neurology & neurosurgeryMuscle Contractiondescription
Adeno-associated virus (AAV)-U7-mediated skipping of dystrophin-exon-23 restores dystrophin expression and muscle function in the mdx mouse model of Duchenne muscular dystrophy. Soluble activin receptor IIB (sActRIIB-Fc) inhibits signaling of myostatin and homologous molecules and increases muscle mass and function of wild-type and mdx mice. We hypothesized that combined treatment with AAV-U7 and sActRIIB-Fc may synergistically improve mdx muscle function. Bioactivity of sActRIIB-Fc on skeletal muscle was first demonstrated in wild-type mice. In mdx mice we show that AAV-U7-mediated dystrophin restoration improved specific muscle force and resistance to eccentric contractions when applied alone. Treatment of mdx mice with sActRIIB-Fc increased body weight, muscle mass and myofiber size, but had little effect on muscle function. Combined treatment stimulated muscle growth comparable to the effect of sActRIIB-Fc alone and dystrophin rescue was similar to AAV-U7 alone. Moreover, combined treatment improved maximal tetanic force and the resistance to eccentric contraction to similar extent as AAV-U7 alone. In conclusion, combination of dystrophin exon skipping with sActRIIB-Fc brings together benefits of each treatment; however, we failed to evidence a clear synergistic effect on mdx muscle function.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-12-31 | Human gene therapy |