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- Title
Optimization of regional intraarterial naked DNA-mediated transgene delivery to skeletal muscles in a large animal model
- Authors
Danialou, Gawiyou; Comtois, Alain S.; Matecki, Stefan; Nalbantoglu, Josephine; Karpati, George; Gilbert, Renald; Geoffroy, Pascale; Gilligan, Sandra; Tanguay, Jean-Francois; Petrof, Basil J.
- Abstract
Abstract: Effective gene therapy for muscular dystrophy will likely require intravascular administration. Although plasmid DNA (pDNA) contained within a large volume and rapidly infused into a major artery can achieve gene transfer within downstream muscles, this is associated with substantial muscle edema. Here we hypothesized that excessive edema-related increases in intramuscular pressure (IM pressure) developed during intraarterial pDNA injections could hinder successful gene delivery. Accordingly, we monitored IM pressure during injection of pDNA carrying a LacZ transgene into the femoral artery of rats and pigs. Large variations in IM pressure were found between different muscles. There was a significant inverse relationship between IM pressure and the subsequent level of gene transfer to muscle. Modification of the injection protocol to reduce IM pressure led to greatly increased pDNA-mediated gene expression and reduced muscle damage in pigs. Under the most optimized conditions, average transfection within eight different muscles of the pig hind limb amounted to 22% of all fibers, attaining a maximum of 60% in the gastrocnemius muscle. We conclude that IM pressure monitoring is a simple and useful procedure, which can be applied in both small and large animals to help optimize pDNA-mediated gene transfer to skeletal muscles by the intraarterial route.
- Subjects
DNA; ANIMAL models in research; MUSCLES; TRANSGENES
- Publication
Molecular Therapy, 2005, Vol 11, Issue 2, p257
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1016/j.ymthe.2004.09.016