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

C Qiao, J Li, T Zhu, R Draviam… - Proceedings of the …, 2005 - National Acad Sciences
C Qiao, J Li, T Zhu, R Draviam, S Watkins, X Ye, C Chen, J Li, X Xiao
Proceedings of the National Academy of Sciences, 2005National Acad Sciences
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 …
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.
National Acad Sciences