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Alternative to Gene Replacement for Duchenne Muscular Dystrophy using Human Alpha7 Integrin (ITGA7)

Heller, Kristin Noreen
http://rave.ohiolink.edu/etdc/view?acc_num=osu1388401639

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
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 investigated an alternative therapeutic approach to dystrophin replacement by overexpressing human a7 integrin (ITGA7) using adeno-associated virus (AAV) delivery. ITGA7 is a laminin receptor in skeletal and cardiac muscle that links the extracellular matrix to the actin skeleton. It is modestly upregulated in DMD muscle and has been proposed to be an important modifier of dystrophic symptoms. We delivered rAAVrh.74.MCK.ITGA7 to the lower limb of mdx mice through isolated limb perfusion of the femoral artery. We demonstrated approximately fifty percent of fibers in the TA and EDL overexpressing a7 integrin at the sarcolemma at six weeks and forty percent of the fibers in the TA and EDL at twelve weeks following AAV gene transfer. The increase in ITGA7 in skeletal muscle significantly protected against loss of force following eccentric contraction- induced injury compared with untreated (contralateral) muscles at both time points. Reversal of additional dystrophic features included reduced Evan's blue dye uptake and increased muscle fiber diameter. Systemic delivery at an early age resulted in widespread expression of ITGA7 in skeletal muscle, reduced kyphosis, increased body weight and an increased muscle fiber diameter in the severe mdx/utrn-/- mouse. The increase in ITGA7 significantly improved specific force in the diaphragm and EDL muscle and significantly protected against loss of force following eccentric contraction- induced injury compared with untreated EDL muscles. Taken together, these data show that rAAVrh.74.MCK.ITGA7 gene transfer demonstrates promise for DMD clinical trials.
Jerry Mendell, MD (Advisor)
Louise Rodino-Klapac, PhD (Committee Member)
Reed Clark, PhD (Committee Member)
Paul Janssen, PhD (Committee Member)
91 p.
Molecular Biology
AAV, DMD, ITGA7, Gene Therapy

Recommended Citations

Citations

  • Heller, K. N. (2014). Alternative to Gene Replacement for Duchenne Muscular Dystrophy using Human Alpha7 Integrin (ITGA7) [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1388401639

    APA Style (7th edition)

  • Heller, Kristin. Alternative to Gene Replacement for Duchenne Muscular Dystrophy using Human Alpha7 Integrin (ITGA7). 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1388401639.

    MLA Style (8th edition)

  • Heller, Kristin. "Alternative to Gene Replacement for Duchenne Muscular Dystrophy using Human Alpha7 Integrin (ITGA7)." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1388401639

    Chicago Manual of Style (17th edition)

osu1388401639
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This open access ETD is published by The Ohio State University and OhioLINK.