Talk abstracts

Talk on Wednesday 11:35-11:50am submitted by Kristin Heller

Overexpression of Human Alpha7 integrin as a potential therapy for Duchenne Muscular Dystrophy

Kristin N. Heller (Department of Molecular, Cellular and Developmental Biology, Center for Gene Therapy, Nationwide Childrens Hospital, Department of Pediatrics), Chrystal L. Montgomery (Center for Gene Therapy, Nationwide Childrens Hospital, Department of Pediatrics), Vinod Malik (Center for Gene Therapy, Nationwide Childrens Hospital, Department of Pediatrics), Paul M. L. Janssen (Department of physiology and cell biology, Ohio State University), K. Reed Clark (Center for Gene Therapy, Nationwide Childrens Hospital and Department of Pediatrics, Ohio State University), Louise R. Rodino-Klapac (Center for Gene Therapy, Nationwide Childrens Hospital and Department of Pediatrics, Ohio State University)

Abstract:
Duchenne Muscular Dystrophy (DMD) is a severe muscle disease caused by mutations in the dystrophin gene. Dystrophin helps link integral membrane proteins to the actin cytoskeleton and stabilizes the sarcolemma during muscle activity. We have focused on a unique approach utilizing adeno-associated virus (AAV) to develop a treatment for DMD using the mdx mouse model. Our strategy involves the upregulation of α7 integrin, a laminin receptor in skeletal and cardiac muscle that links the extracellular matrix to the actin skeleton, similar to that of the dystrophin-glycoprotein complex. α7 has been proposed to be an important modifier of dystrophic symptoms. Burkin et al. showed that transgenic expression of the rat isoform in the mdx/utr -/- promoted satellite cell proliferation and activation, maintenance of muscle integrity, promoted hypertrophy and reduced cardiomyopathy. We have generated rAAV8.MCK.human α7 integrin and delivered it to the lower limb of mdx mice through isolated limb perfusion. As mdx mice have endogenous α7 expression, we measured human α7 as a biomarker of efficacy. Outcome measures include analysis of reversal of pathology and improvement in muscle strength and resistance to eccentric contraction induced injury in the EDL muscle. We have demonstrated approximately fifty percent of fibers in the TA and EDL overexpressing human α7 integrin after delivery through the femoral artery. The increase in human α7 integrin in skeletal muscle significantly protected against loss of force compared with untreated (contralateral) muscles, although measurement of normalized specific force in treated and untreated contralateral mdx EDL muscles show no significant change. α7integrin's protection against eccentric contraction gives hope that this treatment will preserve the muscle phenotype over time and has the benefit of being a non-immunogenic. We are currently treating mdx/utrn-/- mice to determine if there is a similar improvement in muscle physiology and investigating the mechanism that is involved in the protection from eccentric contraction induced injury.

References:
Burkin, D. J., G. Q. Wallace, et al. (2005).

Keywords: Duchenne Muscular Dystrophy, Gene Therapy, Adeno associated virus