1. ¹Department of Neurology, Kumamoto University Graduate School of Medical Science, Kumamoto, Japan
2. ²Laboratory of Pharmacology, Division of Life Science, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan

Correspondence: Yasushi Maeda, Department of Neurology, Kumamoto University Graduate School of Medical Science, 1-1-1 Honjo, Kumamoto 860-0811, Japan. E-mail: yasushim@kumamoto-u.ac.jp

The first two authors contributed equally to this work.

Received 15 May 2007; Accepted 29 October 2007; Published online 4 March 2008.

Abstract

Duchenne muscular dystrophy (DMD) is a fatal, progressive, muscle-wasting disease caused by defects in the dystrophin. No viral vector except the helper-dependent adenovirus vector (HDAdv) can package 14-kilobase (kb) full-length dystrophin complementary DNA (cDNA), and HDAdv is considerably safer than old-generation adenovirus vectors because of the large-size deletion in its genome. We have generated HDAdv that carries myc-tagged murine full-length dystrophin cDNA (HDAdv-myc-mFLdys). We injected it into multiple proximal muscles of 7-day-old utrophin/dystrophin double knockout mice (dko mice) (which typically show symptoms quite similar to human DMD) because the proximal muscles are affected in DMD patients. Eight weeks after the injections, the transduced dystrophin was widely expressed, and we found a significant reduction in centrally nucleated myofibers and the restoration of the dystrophin-associated proteins, -dystroglycan (-DG) and -sarcoglycan (-SG), as well as neuronal nitric oxide synthase (nNOS). The injected dko mice also showed an increase in body weight, an improvement in motor performance, and a prolongation of life span. Using HDAdv, we could treat DMD model mice even by transferring the therapeutic gene into multiple skeletal muscles. Our results suggest that multiple intramuscular administrations of HDAdv carrying full-length dystrophin cDNA may reduce symptoms and compensate for lost functions in DMD patients.