Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 25, Pages 13714-13719Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.240335297
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- NIAMS NIH HHS [R01 AR045967, AR 45926, AR45967, P01 AR045925] Funding Source: Medline
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Duchenne muscular dystrophy (DMD) is the most common and lethal genetic muscle disorder, caused by recessive mutations in the dystrophin gene. One of every 3.500 mates suffers from DMD, yet no treatment is currently available. Genetic therapeutic approaches, using primarily myoblast transplantation and adenovirus-mediated gene transfer, have met with limited success. Adenoassociated virus (AAV) vectors, although proven superior for muscle gene transfer, are too small (5 kb) to package the 14-kb dystrophin cDNA. Here we have created a series of minidystrophin genes (<4.2 kb) under the control of a muscle-specific promoter that readily package into AAV vectors. When injected into the muscle of mdx mice (a DMD model), two of the minigenes resulted in efficient and stable expression in a majority of the myofibers, restoring the missing dystrophin and dystrophin-associated protein complexes onto the plasma membrane. More importantly, this AAV treatment ameliorated dystrophic pathology in mdx muscle and led to normal myofiber morphology, histology, and cell membrane integrity. Thus, we have defined minimal functional dystrophin units and demonstrated the effectiveness of using AAV to deliver the minigenes in vivo, offering a promising avenue for DMD gene therapy.
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