title: Chimeric adeno-associated virus/antisense U1 small nuclear RNA effectively rescues dystrophin synthesis and muscle function by local treatment of mdx mice.
abstract: Duchenne muscular dystrophy (DMD) is a X-linked myopathy in which deletions and point mutations in the dystrophin gene abolish dystrophin expression. The defect can often be corrected at the posttranscriptional level by exon skipping. In an animal model of DMD, the mdx mouse, a point mutation in exon 23 of the dystrophin gene introduces a premature stop codon. Skipping of this exon reestablishes the open reading frame in the dystrophin mRNA. We have obtained persistent exon skipping in mdx mice by local muscle injection of AAV vectors expressing antisense sequences fused to either U1 or U7 small nuclear RNA (snRNA). In the transduced muscles, dystrophin expression, amelioration of muscle morphology, and significant force recovery were obtained. These data indicate that the expression of antisense snRNAs, combined with their efficient muscular delivery through AAV vectors, is a powerful strategy for the therapeutic treatment of DMD. Like U7 snRNA, spliceosomal U1 snRNA is also a suitable backbone for the expression of antisense molecules active in exon skipping.
authors.affiliation: Department of Genetics and Molecular Biology, Institute Pasteur Cenci-Bolognetti, and IBPM, University La Sapienza, 00185 Rome, Italy.
authors.forename: Michela Alessandra
authors.initials: MA
authors.lastname: Denti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rosa
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Antona
authors.forename: Olga
authors.initials: O
authors.lastname: Sthandier
authors.forename: Fernanda Gabriella
authors.initials: FG
authors.lastname: De Angelis
authors.forename: Carmine
authors.initials: C
authors.lastname: Nicoletti
authors.forename: Mariacarmela
authors.initials: M
authors.lastname: Allocca
authors.forename: Orietta
authors.initials: O
authors.lastname: Pansarasa
authors.forename: Valeria
authors.initials: V
authors.lastname: Parente
authors.forename: Antonio
authors.initials: A
authors.lastname: Musarò
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
authors.forename: Roberto
authors.initials: R
authors.lastname: Bottinelli
authors.forename: Irene
authors.initials: I
authors.lastname: Bozzoni
mesh_terms: D000818:Animals; D001483:Base Sequence; D004274:DNA, Recombinant; D000229:Dependovirus / Q000235:genetics*; D016189:Dystrophin / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors; D007273:Injections, Intramuscular; D051379:Mice; D018101:Mice, Inbred mdx / Q000235:genetics; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009137:Muscular Dystrophy, Animal / Q000628:therapy*; D016372:RNA, Antisense / Q000627:therapeutic use; D012342:RNA, Small Nuclear / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use
chemical_list: D004274:DNA, Recombinant; D016189:Dystrophin; D016372:RNA, Antisense; D012342:RNA, Small Nuclear; D011993:Recombinant Fusion Proteins; C405483:U1 small nuclear RNA; C405487:U7 small nuclear RNA