Functional evaluation of the reversibility of muscular dystrophy in the mdx mouse via dystrophin restoration.

摘要

Duchenne muscular dystrophy (DMD), a degenerative, lethal muscle disorder and the most common form of MD, is caused by mutations in the dystrophin gene. Transgenic and adenoviral vector technologies have demonstrated the feasibility of gene therapy for DMD by the restoration of dystrophin and subsequent prevention of the development of dystrophy in skeletal muscles of the dystrophin-deficient mdx mouse, a model of DMD. However, the ability to halt and reverse muscle deterioration once the disease has progressed remains unclear.; The primary goal of this research was to examine the potential for reversal of functional deficiencies in the mdx mouse. Muscles of mdx mice lack dystrophin and as a result are more susceptible to contraction-induced damage than muscles from control mice. An in situ assay that reveals the high susceptibility to injury of dystrophic limb muscles was developed and utilized to characterize the extent of muscle damage in mdx and control mice at different ages. In an attempt to reduce the susceptibility to injury, the restoration of full-length dystrophin to muscles of adult mdx mice was achieved by delivery with gutted adenoviral vectors that are devoid of all viral genes. High level expression of dystrophin corrected the susceptibility to contraction-induced injury in muscles of mdx mice by 40%. These studies demonstrated (1) the ability of adenoviral vectors to transduce muscles of adult, immunocompetent, mdx mice and (2) that expression of virally-delivered full-length dystrophin partially reverses the major pathophysiological abnormality of dystrophic muscle. The results from this research will help further the development of gene therapy for muscular dystrophy.