Format

Send to

Choose Destination
See comment in PubMed Commons below
Mol Ther. 2010 Aug;18(8):1501-8. doi: 10.1038/mt.2010.94. Epub 2010 Jun 1.

Widespread muscle expression of an AAV9 human mini-dystrophin vector after intravenous injection in neonatal dystrophin-deficient dogs.

Author information

1
Department of Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, USA. joe_kornegay@med.unc.edu

Abstract

Duchenne (DMD) and golden retriever (GRMD) muscular dystrophy are caused by genetic mutations in the dystrophin gene and afflict striated muscles. We investigated systemic gene delivery in 4-day-old GRMD dogs given a single intravenous injection of an AAV9 vector (1.5 x 10(14) vector genomes/kg) carrying a human codon-optimized human mini-dystrophin gene under control of the cytomegalovirus (CMV) promoter. One of the three treated dogs was euthanized 9 days later due to pre-existing conditions. Scattered mini-dystrophin-positive myofibers were seen by immunofluorescent (IF) staining in numerous muscles. At the end of the 16-week study, the other two dogs showed generalized muscle expression of mini-dystrophin in ~15% to nearly 100% of myofibers. Western blot and vector DNA quantitative PCR results agreed with the IF data. Delayed growth and pelvic limb muscle atrophy and contractures were seen several weeks after vector delivery. T-2 weighted magnetic resonance imaging (MRI) at 8 weeks showed increased signal intensity compatible with inflammation in several pelvic limb muscles. This marked early inflammatory response raised concerns regarding methodology. Use of the ubiquitous CMV promoter, extra-high vector dose, and marked expression of a human protein in canine muscles may have contributed to the pathologic changes seen in the pelvic limbs.

PMID:
20517298
PMCID:
PMC2927072
DOI:
10.1038/mt.2010.94
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center