Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model.
Duchenne muscular dystrophy is an X-linked muscle disease characterized by mutations in the dystrophin gene. Many of these can be corrected at the posttranscriptional level by skipping the mutated exon. We have obtained persistent exon skipping in mdx mice by tail vein injection with an adeno-associated viral (AAV) vector expressing antisense sequences as part of the stable cellular U1 small nuclear RNA. Systemic delivery of the AAV construct resulted in effective body-wide colonization, significant recovery of the functional properties in vivo, and lower creatine kinase serum levels, suggesting an overall decrease in muscle wasting. The transduced muscles rescued dystrophin expression and displayed a significant recovery of function toward the normal values at single muscle fiber level. This approach provides solid bases for a systemic use of AAV-mediated antisense-U1 small nuclear RNA expression for the therapeutic treatment of Duchenne muscular dystrophy.
Denti
Michela Alessandra
MA
Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology, University La Sapienza, P. le Aldo Moro 5, 00185 Rome, Italy.
Rosa
Alessandro
A
D'Antona
Giuseppe
G
Sthandier
Olga
O
De Angelis
Fernanda Gabriella
FG
Nicoletti
Carmine
C
Allocca
Mariacarmela
M
Pansarasa
Orietta
O
Parente
Valeria
V
Musarò
Antonio
A
Auricchio
Alberto
A
Bottinelli
Roberto
R
Bozzoni
Irene
I
D000818:Animals; D001483:Base Sequence; D000229:Dependovirus / Q000235:genetics; D016189:Dystrophin / Q000235:genetics; D005091:Exons; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D012342:RNA, Small Nuclear / Q000235:genetics
D016189:Dystrophin; D020319:Oligodeoxyribonucleotides, Antisense; D012342:RNA, Small Nuclear; C405483:U1 small nuclear RNA