Research Article: Functional Substitution by TAT-Utrophin in Dystrophin-Deficient Mice

Date Published: May 26, 2009

Publisher: Public Library of Science

Author(s): Kevin J. Sonnemann, Hanke Heun-Johnson, Amy J. Turner, Kristen A. Baltgalvis, Dawn A. Lowe, James M. Ervasti, Kay Davies

Abstract: James Ervasti and colleagues show that injection of a truncated form of utrophin transduced all tissues examined, integrated with members of the dystrophin complex, and reduced serum levels of creatine kinase in a mouse model of muscular dystrophy.

Partial Text: Duchenne muscular dystrophy (DMD) is the most prevalent form of human muscular dystrophy and is caused by mutations in dystrophin, a 427 kDa cytoskeletal protein necessary for proper membrane stability in muscle [1]. Although recent advances in cell-, gene-, oligonucleotide-, and small molecule-based therapies have identified several promising approaches to counteract the effects of dystrophin deficiency in animal models [2]–[9], there are currently no effective therapies for humans with DMD. We have chosen to pursue the therapeutic potential of utrophin (Utr), an autosomal homolog of dystrophin that corrects all known phenotypes of the dystrophin-deficient mdx mouse when transgenically overexpressed to sufficient levels [10]. Our ability to express and purify scalable quantities of recombinant full-length and truncated utrophins [11], combined with the availability of cell-penetrating peptides, provides an attractive potential method for directly boosting utrophin levels in vivo.

Our experiments are, to our knowledge, the first to demonstrate the feasibility and efficacy of direct protein replacement to combat the effects of dystrophin deficiency in mdx mice, an established model of Duchenne muscular dystrophy in humans. IP injections of the cell-penetrating TAT-μUtr restored proper membrane targeting of dystrophin protein complex members, stabilized muscle membrane integrity, attenuated histological hallmarks of dystrophy, and conferred functional benefits to treated muscle.



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