Optimization of Regional Intraarterial Naked DNA-Mediated
Transgene Delivery to Skeletal Muscles in a Large Animal Model
Gawiyou
Danialou,Alain S. Comtois,Stefan Matecki, Josephine Nalbantoglu, George
Karpati, Renald Gilbert, Pascale Geoffroy, Sandra Gilligan, Jean-Francois
Tanguay, and Basil J. Petrof - Canada
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.