We delivered plasmid
DNA encoding therapeutic genes to the muscles of mouse models of
limb girdle muscular dystrophy (LGMD) 2A, 2B, and 2D, deficient in calpain3,
dysferlin, and
alpha-sarcoglycan, respectively. We also delivered the human
follistatin gene, which has the potential to increase therapeutic benefit. After
intramuscular injection of
DNA, electroporation was applied to enhance delivery to muscle fibers. When plasmids encoding the human calpain3 or
dysferlin cDNA sequences were injected into quadriceps muscles of
LGMD2A and
LGMD2B mouse models, respectively, in 3-month studies, robust levels of calpain3 and
dysferlin proteins were detected. We observed a statistically significant decrease in
Evans blue dye penetration in
LGMD2B mouse muscles after delivery of the
dysferlin gene, consistent with repair of the muscle membrane defect in these mice. The therapeutic value of delivery of the genes for
alpha-sarcoglycan and
follistatin was documented by significant drops in
Evans blue dye penetration in gastrocnemius muscles of
LGMD2D mice. These results indicated for the first time that a combined gene therapy involving both
alpha-sarcoglycan and
follistatin would be valuable for
LGMD2D patients. We suggest that this non-viral gene delivery method should be explored for its translational potential in patients.