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. 2006 Jul;12(7):787-9.
doi: 10.1038/nm1439. Epub 2006 Jul 2.

rAAV6-microdystrophin Preserves Muscle Function and Extends Lifespan in Severely Dystrophic Mice

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Free PMC article

rAAV6-microdystrophin Preserves Muscle Function and Extends Lifespan in Severely Dystrophic Mice

Paul Gregorevic et al. Nat Med. .
Free PMC article

Abstract

Mice carrying mutations in both the dystrophin and utrophin genes die prematurely as a consequence of severe muscular dystrophy. Here, we show that intravascular administration of recombinant adeno-associated viral (rAAV) vectors carrying a microdystrophin gene restores expression of dystrophin in the respiratory, cardiac and limb musculature of these mice, considerably reducing skeletal muscle pathology and extending lifespan. These findings suggest rAAV vector-mediated systemic gene transfer may be useful for treatment of serious neuromuscular disorders such as Duchenne muscular dystrophy.

Figures

Figure 1
Figure 1
Systemic administration of rAAV6-microdystrophin enhances the structural and functional properties of respiratory muscles in dystrophic mice. (a) Restoration of dystrophin expression (green, left column) throughout the diaphragm muscle of a treated mouse (Tdko) contributes to improved muscle fiber size and organization (laminin and nuclei - red and blue respectively in middle panel; eosin and hematoxylin – pink and purple respectively in right column), as compared with the muscles of an untreated dystrophic mouse (dko), and a wildtype mouse (wt). Scale bar represents 100 μm. (b) Treatment restored dystrophin expression in the vast majority of diaphragm myofibers of treated mice (red), in contrast with no expression in the muscles of untreated mice (grey) and comprehensive expression in the muscles of wildtype mice (black). (c) Dystrophin-positive myofibers of treated diaphragm muscles (yellow) were less frequently small in size (mean myofiber diameter; wildtype, 22.1 ± 0.7, dystrophic, 14.9 ± 0.7, treated - dystrophin-positive fibers, 23.2 ± 1 μm), and (d) centrally-nucleated compared with the myofibers in the muscles of untreated mice. (e) Treatment also improved the peak isometric force-producing capacity of diaphragm muscles as normalized for cross-sectional area. (f) Contractile performance after consecutive eccentric contractions of progressively increasing strain (identified as % beyond optimal muscle length, and expressed in terms of force relative to respective initial output), demonstrates that treatment essentially corrects the susceptibility to contraction-induced injury otherwise observed in dystrophic diaphragm muscles.
Figure 2
Figure 2
Systemic rAAV6-microdystrophin administration improves limb muscle function and extends the lifespan of dystrophic mice. (a) Dystrophin expression was restored in the majority of the myofibers comprising the Tibialis anterior muscles of mice examined 18 weeks after treatment (red), compared with the muscles of untreated dystrophic (grey) and wildtype (black) mice. (b) Dystrophin-positive myofibers in the muscles of treated mice (yellow) tended to be larger in diameter, (c) and less frequently centrally-nucleated than cells in the muscles of untreated mice. (d) Treatment was associated with an increased TA muscle mass, (e) and peak isometric force-producing capacity compared with untreated muscles (though unchanged specific force; wt, 240 ± 11, dko, 149 ± 5, Tdko, 145 ± 6 kN/m2). (f) Contractile performance expressed in terms of absolute force (upper) and performance relative to initial output (lower) demonstrates that the muscles of treated mice exhibit improved force output and resistance to contraction-induced injury when subjected to consecutive eccentric contractions of progressively increasing strain (identified as % beyond optimal muscle length). (g) Creatine kinase activity as measured in serum is markedly reduced in treated mice compared with untreated mice, yet remains moderately elevated compared with non-dystrophic animals. (h) Body mass (upper panel) in treated mice is increased compared with untreated animals, and comparable with the mass of wildtype mice. In cohorts monitored for lifespan (lower panel), treated mice (n = 8) live significantly longer than untreated mice (n = 70). (i) Untreated mice typically exhibit significant muscle wasting and kyphotic posture by 16 weeks of age, while treated mice retain considerably greater muscularity.

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