Published online on February 24, 2006, 10.1073/pnas.0508917103
Medical Sciences
Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model
( exon skipping |
adeno-associated virus vectors |
antisense |
small nuclear RNA |
dystrophin )
Michela Alessandra Denti *, Alessandro Rosa *, Giuseppe D'Antona 
, Olga Sthandier *, Fernanda Gabriella De Angelis *, Carmine Nicoletti 
, Mariacarmela Allocca 
, Orietta Pansarasa , Valeria Parente , Antonio Musarò , Alberto Auricchio , Roberto Bottinelli , and Irene Bozzoni *¶
*Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and Institute of Molecular Biology and Pathology, University "La Sapienza," P. le Aldo Moro 5, 00185 Rome, Italy; Department of Experimental Medicine, Human Physiology Unit, University of Pavia, Via Forlanini 6, 27100 Pavia, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131 Naples, Italy; and Department of Histology and Medical Embryology, Centro di Eccellenza di Biologia e Medicina Molecolare and Interuniversity Institute of Myology, University of Rome "La Sapienza," Via A. Scarpa 14, 00161 Rome, Italy
Edited by Louis M. Kunkel, Harvard Medical School, Boston, MA, and approved January 6, 2006 (received for review October 12, 2005)
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.
Author contributions: M.A.D., A.R., G.D., F.G.D.A., A.M., A.A., R.B., and I.B. designed research; M.A.D., A.R., G.D., O.S., F.G.D.A., C.N., M.A., O.P., V.P., and A.A. performed research; M.A.D., A.R., G.D., O.S., F.G.D.A., A.M., A.A., R.B., and I.B. analyzed data; and M.A.D., A.R., G.D., F.G.D.A., A.M., A.A., R.B., and I.B. wrote the paper.
Conflict of interest statement: No conflicts declared.
¶To whom correspondence should be addressed.
Irene Bozzoni, E-mail: irene.bozzoni{at}uniroma1.it
www.pnas.org/cgi/doi/10.1073/pnas.0508917103
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg What's this?
This article has been cited by other articles in HighWire Press-hosted journals:
|
|
|
|
 
M. Pinotti, L. Rizzotto, D. Balestra, M. A. Lewandowska, N. Cavallari, G. Marchetti, F. Bernardi, and F. Pagani
U1-snRNA-mediated rescue of mRNA processing in severe factor VII deficiency
Blood,
March 1, 2008;
111(5):
2681 - 2684.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. D'Antona, L. Brocca, O. Pansarasa, C. Rinaldi, R. Tupler, and R. Bottinelli
Structural and functional alterations of muscle fibres in the novel mouse model of facioscapulohumeral muscular dystrophy
J. Physiol.,
November 1, 2007;
584(3):
997 - 1009.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Morel-Verdebout, S. Botteron, and S. Kiliaridis
Dentofacial characteristics of growing patients with Duchenne muscular dystrophy: a morphological study
Eur J Orthod,
October 1, 2007;
29(5):
500 - 507.
[Abstract]
[Full Text]
[PDF]
|
|
|
