Gene therapy for renal anemia in mice with polycystic kidney using an adenovirus vector encoding the human erythropoietin gene

BACKGROUND: Recombinant human erythropoietin (rHuEPO) is primarily used for patients with anemia associated with end-stage renal disease. We evaluated the efficacy of EPO gene therapy using adenovirus vector for chronic renal failure mice expressing severe renal anemia. METHODS: Recombinant HuEPO gene transfer to mesothelial cells was performed in vitro and in vivo. Recombinant replication-deficient adenoviruses containing rHuEPO cDNA (AdCMVEPO), E. coli lacZ gene (AdCMVlacZ), or an nonexogenous gene (AdNull as control vector) driven by the cytomegalovirus promotor/enhancer were constructed. The oligosaccharides associated with the rHuEPO from AdCMVEPO-treated mesothelial cells were analyzed. For in vivo study, the DBA/2FG-pcy mouse, a model for human autosomal recessive polycystic kidney disease resulting in chronic renal failure with progressive anemia, was used. RESULTS: The sialylated oligosaccharides associated with the rHuEPO produced in AdCMVEPO-treated mesothelial cells occupied 78 +/- 0.7% of the total oligosaccharide pool. A single intraperitoneal administration of AdCMVEPO induced rHuEPO synthesis in the peritoneal cells and a marked increase in erythrocyte production. The maximal increase in hematocrit (43 +/- 4%) was observed on day 28, and it remained elevated for 40 days. CONCLUSION: These results indicate that intraperitoneal administration of AdCMVEPO improves renal anemia in mice with chronic renal failure and that the mesothelial cell is an appropriate target cell for gene transfer.