title: In vivo delivery of naked antisense oligos in aged mdx mice: analysis of dystrophin restoration in skeletal and cardiac muscle.
abstract: Antisense-mediated exon skipping holds great potential for the treatment of DMD. In mdx mice, functional recovery of skeletal muscle has been obtained upon systemic delivery of "naked" oligonucleotides or viral vectors encoding for antisense snRNAs. However, amongst the studies reported so far, which used either neonatal or young adult animals--only one achieved dystrophin restoration in cardiac muscle, using an adeno-associated vector. Here we report the in vivo delivery of morpholino oligos in aged mdx mice, both in skeletal muscle, via intra-arterial injection, and in cardiac muscle, via intra-muscular injection. Localized intra-arterial delivery yielded high levels of dystrophin restoration and just two doses of 100 microg each resulted into detectable force recovery in the EDL muscles of treated limbs. On the other hand, upon intra-cardiac injections in the left ventricle wall the skipping effect was much lower than what obtained in tibialis anterior muscles injected with comparable amounts of oligos. This latter finding suggests that even upon direct delivery antisense-mediated dystrophin restoration in cardiac muscle might suffer from limitations that do not exist in skeletal muscle.
authors.affiliation: Department of Biology, University of Padova, via U. Bassi 58/B, 35121 Padova, Italy. libero.vitiello@bio.unipd.it
authors.forename: Libero
authors.initials: L
authors.lastname: Vitiello
authors.forename: Nicola
authors.initials: N
authors.lastname: Bassi
authors.forename: Paola
authors.initials: P
authors.lastname: Campagnolo
authors.forename: Eva
authors.initials: E
authors.lastname: Zaccariotto
authors.forename: Gianluca
authors.initials: G
authors.lastname: Occhi
authors.forename: Alberto
authors.initials: A
authors.lastname: Malerba
authors.forename: Sarah
authors.initials: S
authors.lastname: Pigozzo
authors.forename: Carlo
authors.initials: C
authors.lastname: Reggiani
authors.forename: Simonetta
authors.initials: S
authors.lastname: Ausoni
authors.forename: Tania
authors.initials: T
authors.lastname: Zaglia
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Gamba
authors.forename: Maurizio D
authors.initials: MD
authors.lastname: Baroni
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Ditadi
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D003627:Data Interpretation, Statistical; D016189:Dystrophin / Q000096:biosynthesis* / Q000235:genetics*; D005091:Exons / Q000235:genetics; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects; D007150:Immunohistochemistry; D007269:Injections, Intra-Arterial; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016189:Dystrophin; D016376:Oligonucleotides, Antisense