Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model.
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ABSTRACT:
SUBMITTER: Denti MA
PROVIDER: S-EPMC1450150 | biostudies-literature | 2006 Mar
REPOSITORIES: biostudies-literature
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Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model.
Denti Michela Alessandra MA 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
Proceedings of the National Academy of Sciences of the United States of America 20060224 10
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, signifi ...[more]
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Project description:Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by mutations in the dystrophin gene, leading to the loss of a critical component of the sarcolemmal dystrophin glycoprotein complex. Galectin-1 is a small 14 kDa protein normally found in skeletal muscle and has been shown to be a modifier of immune response, muscle repair, and apoptosis. Galectin-1 levels are elevated in the muscle of mouse and dog models of DMD. Together, these findings led us to hypothesize that Galectin-1 may serve as a modifier of disease progression in DMD. To test this hypothesis, recombinant mouse Galectin-1 was produced and used to treat myogenic cells and the mdx mouse model of DMD. Here we show that intramuscular and intraperitoneal injections of Galectin-1 into mdx mice prevented pathology and improved muscle function in skeletal muscle. These improvements were a result of enhanced sarcolemmal stability mediated by elevated utrophin and α7β1 integrin protein levels. Together our results demonstrate for the first time that Galectin-1 may serve as an exciting new protein therapeutic for the treatment of DMD.
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