title: Amelioration of laminin-alpha2-deficient congenital muscular dystrophy by somatic gene transfer of miniagrin.
abstract: Congenital muscular dystrophy (CMD) is characterized by severe muscle wasting, premature death in early childhood, and lack of effective treatment. Most of the CMD cases are caused by genetic mutations of laminin-alpha2, which is essential for the structural integrity of muscle extracellular matrix. Here, we report that somatic gene delivery of a structurally unrelated protein, a miniature version of agrin, functionally compensates for laminin-alpha2 deficiency in the murine models of CMD. Adeno-associated virus-mediated overexpression of miniagrin restored the structural integrity of myofiber basal lamina, inhibited interstitial fibrosis, and ameliorated dystrophic pathology. Furthermore, systemic gene delivery of miniagrin into multiple vital muscles significantly improved whole body growth and motility and quadrupled the lifespan (50% survival) of the dystrophic mice. Thus, our study demonstrated the efficacy of somatic gene therapy in a mouse model of CMD.
authors.affiliation: Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Chunping
authors.initials: C
authors.lastname: Qiao
authors.forename: Jianbin
authors.initials: J
authors.lastname: Li
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Romesh
authors.initials: R
authors.lastname: Draviam
authors.forename: Simon
authors.initials: S
authors.lastname: Watkins
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Ye
authors.forename: Chunlian
authors.initials: C
authors.lastname: Chen
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
mesh_terms: D018171:Agrin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers; D000229:Dependovirus; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D007797:Laminin / Q000172:deficiency; D008124:Locomotion; D008136:Longevity; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009136:Muscular Dystrophies / Q000151:congenital / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D021382:Protein Sorting Signals / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D018171:Agrin; D017931:DNA Primers; D007797:Laminin; D021382:Protein Sorting Signals; C102645:laminin alpha 2; C507258:miniagrin protein, mouse