Duchenne muscular dystrophy is caused by a genetic defect in the
dystrophin gene. The absence of
dystrophin results in muscle fiber
necrosis and regeneration, leading to progressive muscle fiber loss.
Utrophin is a close analogue of
dystrophin. A substantial, ectopic expression of
utrophin in the extrasynaptic sarcolemma of
dystrophin-deficient muscle fibers can prevent deleterious effects of
dystrophin deficiency. An alternative approach for the extrasynaptic up-regulation of
utrophin involves the augmentation of
utrophin transcription via the endogenous
utrophin A promoter using custom-designed transcriptional activator
proteins with zinc finger (ZFP) motifs. We tested a panel of custom-designed ZFP for their ability to activate the
utrophin A promoter. Expression of one such ZFP efficiently increased, in a time-dependent manner,
utrophin transcript and
protein levels both in vitro and in vivo. In dystrophic mouse (mdx) muscles, administration of adenoviral vectors expressing this ZFP led to significant enhancement of muscle function with decreased
necrosis, restoration of the
dystrophin-associated proteins, and improved resistance to eccentric contractions. These studies provide evidence that specifically designed ZFPs can act as strong transcriptional activators of the
utrophin A promoter. These may thus serve as attractive therapeutic agents for
dystrophin deficiency states such as
Duchenne muscular dystrophy.