Amelioration of laminin-α2-deficient congenital muscular dystrophy by somatic gene transfer of miniagrin

doi:10.1073/pnas.0502137102

Amelioration of laminin-α2-deficient congenital muscular dystrophy by somatic gene transfer of miniagrin

Departments of ^*Orthopedic Surgery, ^‡Molecular Genetics and Biochemistry, and ^†Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261

Edited by Kevin P. Campbell, University of Iowa, Iowa City, IA, and approved June 25, 2005 (received for review March 15, 2005)

Abstract

Congenital muscular dystrophy (CMD) is characterized by severe muscle wasting, premature death in early childhood, and lack of effective treatment. Most of the CMD cases are caused by genetic mutations of laminin-α2, which is essential for the structural integrity of muscle extracellular matrix. Here, we report that somatic gene delivery of a structurally unrelated protein, a miniature version of agrin, functionally compensates for laminin-α2 deficiency in the murine models of CMD. Adeno-associated virus-mediated overexpression of miniagrin restored the structural integrity of myofiber basal lamina, inhibited interstitial fibrosis, and ameliorated dystrophic pathology. Furthermore, systemic gene delivery of miniagrin into multiple vital muscles significantly improved whole body growth and motility and quadrupled the lifespan (50% survival) of the dystrophic mice. Thus, our study demonstrated the efficacy of somatic gene therapy in a mouse model of CMD.

Footnotes

↵ § To whom correspondence should be addressed. E-mail: xiaox{at}pitt.edu.
Author contributions: C.Q., T.Z., Jianbin Li, S.W., X.Y., Juan Li, and X.X. designed research; C.Q., T.Z., Jianbin Li, R.D., S.W., X.Y., C.C., Juan Li, and X.X. performed research; C.Q., T.Z., Jianbin Li, R.D., S.W., X.Y., Juan Li, and X.X. contributed new reagents/analytic tools; C.Q., T.Z., Jianbin Li, R.D., S.W., X.Y., Juan Li, and X.X. analyzed data; and C.Q., T.Z., X.Y., Juan Li, and X.X. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: CMD, congenital muscular dystrophy; AAV, adeno-associated virus; IF, immunofluorescent; H&E, hematoxylin/eosin.
Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AY914875).