Abstract:
:Rescue of dystrophic skeletal muscle in mdx and utrophin/dystrophin-deficient (dko) mouse models by reintroduction of dystrophin has validated gene therapy as a potential therapeutic approach for Duchenne muscular dystrophy. However, the size of the dystrophin gene exceeds the capacity of adeno-associated viral (AAV) vectors. Dystrophin provides a mechanical link at the muscle membrane by direct binding of its amino-terminal and cysteine-rich domains to actin and a transmembrane protein complex, respectively. It has not been investigated whether restoration of these two tethering functions by two separate dystrophin molecules is sufficient to prevent dystrophic pathologies. We examine the effect of coexpression of the amino-terminal and cysteine-rich domains from separate dystrophin transgenes, Deltacys and Dp71, on the dystrophic phenotype. Expression of individual dystrophin domains from multiple vectors would effectively expand AAV capacity. Although both Deltacys and Dp71 colocalize at the membrane, there is no improvement of dystrophic pathology. The fiber-type and neuromuscular junction abnormalities of dko mice that are ameliorated by the Deltacys transgene are not further improved or disrupted by Dp71. Separate truncated dystrophins, which together restore all protein interactions and scaffolding for signaling molecules, are not sufficient to ameliorate the dystrophic phenotype and therefore dystrophin domains in trans cannot be used to increase the effective cloning capacity for AAV-mediated gene therapy.
journal_name
Gene Therjournal_title
Gene therapyauthors
Gardner KL,Kearney JA,Edwards JD,Rafael-Fortney JAdoi
10.1038/sj.gt.3302686subject
Has Abstractpub_date
2006-05-01 00:00:00pages
744-51issue
9eissn
0969-7128issn
1476-5462pii
3302686journal_volume
13pub_type
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