Erythropoietin secretion and physiological effect in mouse after intramuscular plasmid DNA electrotransfer

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Abstract
Direct intramuscular plasmid DNA injection has recently been proposed for erythropoietin therapy, as an alternative to either systemic injection of recombinant erythropoietin or the use of viral vectors for erythropoietin gene transfer. However, direct intramuscular plasmid injection has so far been hampered by low efficiency and high interindividual variability. We explored the use of a new method termed 'intramuscular electrotransfer' for erythropoietin gene expression in the mouse. This method is based on intramuscular plasmid injection followed by application of appropriate electric pulses. Intramuscular plasmid electrotransfer in mouse leg led to an increase of approximately 10- to 100-fold in circulating murine erythropoietin level, as compared to naked DNA alone. Using electrotransfer, as little as 1 microgram of an erythropoietin encoding plasmid was sufficient to induce an increase in mouse hematocrit, from 47% up to 80%. This hematocrit increase was stable for at least two months. Moreover, interindividual hematocrit variability was markedly reduced by electrotransfer, as compared with naked DNA injection. In vivo electrotransfer appears to be a convenient method for obtaining high erythropoietin expression in mice, and it could also be used for the expression of other secreted therapeutic proteins.