Targeting artificial transcription factors to the utrophin A promoter : Effects on dystrophic pathology and muscle function

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DOIResolve DOI: http://doi.org/10.1074jbcM804518200
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TypeArticle
Journal titleJournal Of Biological Chemistry
Volume283
Issue50
Pages3472034727; # of pages: 8
Subjectbio; deficiency; Dystrophin; In Vitro; Muscle Fibers; Muscles; Muscular Dystrophies; pathology; Protein; Proteins; Transcription Factors; Vitro; Zinc; Up-Regulation
AbstractDuchenne 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.
Publication date
LanguageEnglish
AffiliationNRC Biotechnology Research Institute; National Research Council Canada (NRC-CNRC)
Peer reviewedNo
NRC number47829
NPARC number12400996
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Record identifier1ce58674-c7d4-48ff-a4b3-4d8c6e417e29
Record created2009-10-02
Record modified2016-05-09
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