H. Maruyama et al., Long-term production of erythropoietin after electroporation-mediated transfer of plasmid DNA into the muscles of normal and uremic rats, GENE THER, 8(6), 2001, pp. 461-468
The anemia associated with chronic renal failure is one of the best target
diseases for erythropoietin (Epo) gene transfer. We previously reported a s
hort-term (1 month) study of continuous rat Epo delivery by muscle-targeted
gene transfer of plasmid DNA expressing rat Epo (pCAGGS-Epo) using in vivo
electroporation in normal rats. Here, we performed a long-term pharmacokin
etic study of continuous Epo delivery by this method in normal rats and ure
mic five-sixths nephrectomized rats. In normal rats, Epo gene expression an
d sufficient erythropoiesis occurred with Epo gene transfer in a dose-depen
dent manner, and persisted for at least 11 weeks. Repeated administration o
f the plasmid DNA effectively produced erythropoiesis. Similar erythropoies
is was observed in the uremic rats, and persisted for more than 15 weeks. B
oth normal and uremic rats showed a significant decrease in platelet count.
Moreover, the uremic rats showed Epo-induced hypertension, which is the ma
jor side-effect of recombinant human Epo. These results demonstrate that mu
scle-targeted pCAGGS-Epo transfer by in vivo electroporation is a useful pr
ocedure for the long-term continuous delivery of Epo in both normal and ure
mic rats.