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Gene therapy reverses genetic mutation responsible for heart failure in muscular dystrophy

an lead to severe damage and weakness to muscles, particularly around the hips and shoulders--hence the name "limb girdle"-- as well as in the heart. Like humans, hamsters with this particular delta-sarcoglycan gene defect have severe muscle wasting and weakness and significantly shortened lifespans due to cardiac and respiratory failure.

After injecting a very high dose of AAV-8 carrying a normal copy of the delta-sarcoglycan gene intravenously into 10-day-old and adult LGMD hamsters, Dr. Xiao and his colleagues found that it had been systemically incorporated into skeletal, diaphragm and cardiac muscle cells in both groups. More importantly, cardiac and lung muscle cells in both newborn- and adult-treated hamsters were able to express the normal protein almost a year later. There were dramatic biochemical and structural improvements in muscle cells in both groups as well.

This was accompanied by markedly improved skeletal and cardiac muscle functions. Indeed, the newborn-treated hamsters had completely normal hearts, when examined at eight and one-half months after gene therapy. The adult hamsters also showed significant improvements in heart muscle structure. In contrast, untreated hamsters had severe structural and tissue abnormalities of the heart in addition to secondary symptoms of heart failure such as liver problems, swollen lungs and a severe buildup of fluid in the chest and peritoneal cavities.

Perhaps even more impressive was the improvement in endurance and lifespan of the treated versus the untreated hamsters. The AAV-8-treated hamsters were able to run the same distance as normal hamsters before tiring and for much longer than untreated LGMD hamsters. Furthermore, all of the untreated LGMD animals died of heart failure or other complications of muscular dystrophy around 37 weeks, while all of the AAV-8-treated LGMD hamsters survived beyond the 48-week duration of the study.

"When we began the experiment, we anticipated
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Source:University of Pittsburgh Medical Center


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