title: Rescue from respiratory dysfunction by transduction of full-length dystrophin to diaphragm via the peritoneal cavity in utrophin/dystrophin double knockout mice.
abstract: Duchenne muscular dystrophy (DMD) is an inherited severe muscle wasting disorder with, thus far, no effective therapy. DMD causes respiratory and cardiac failure as well as muscle wastage. Among the various symptoms, respiratory insufficiency is a major cause of death in DMD patients at about 20 years of age. So, naturally, the improvement of respiratory function will extend the patient's life. We report here, for the first time, a sensitive procedure using whole-body plethysmography to monitor respiratory parameters detected in the utrophin/dystrophin double knockout mouse (dko mouse), showing quite similar systemic symptoms to human DMD including restrictive ventilatory impairment. Furthermore, we show that a highly efficient dystrophin-transduction to the dko's diaphragm--achieved by simple intraperitoneal injection of a helper-dependent adenovirus vector (HDAdv) containing the full-length dystrophin expression cassette--provided beneficial results. In spite of dystrophin expression only in the diaphragm, this focal gene transfer could result in the rescue from ventilatory impairment (increased tidal volume (TV) and improvement of compensatory hyperpnea). Our result suggests that a DMD patient's mortal ventilatory impairment may be improved via technically easy means through the intraperitoneal injection of HDAdv.
authors.affiliation: Department of Neurology, Neuroscience, Advanced Biomedical Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ishizaki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Maeda
authors.forename: Ryoko
authors.initials: R
authors.lastname: Kawano
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Suga
authors.forename: Yuji
authors.initials: Y
authors.lastname: Uchida
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Uchino
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.forename: En
authors.initials: E
authors.lastname: Kimura
authors.forename: Makoto
authors.initials: M
authors.lastname: Uchino
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D003964:Diaphragm / Q000378:metabolism*; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009137:Muscular Dystrophy, Animal / Q000628:therapy; D010529:Peritoneal Cavity; D014161:Transduction, Genetic / Q000379:methods*; D049411:Utrophin / Q000235:genetics*
chemical_list: D016189:Dystrophin; D049411:Utrophin