Therapy of anemia in kidney failure, using plasmid encoding erythropoietin.
Numerous studies using erythropoietin (EPO) gene delivery vectors, either viral or nonviral, have shown uncontrolled EPO expression leading to transient or sustained erythrocytosis and, more recently, severe autoimmune anemia. Therefore, there is a need to develop other EPO gene delivery systems that allow sustained and adjustable expression of EPO. We have examined a new approach of delivering plasmid encoding mouse EPO cDNA into mouse skeletal muscle, using an amphiphilic block copolymer. Repeated injections of low doses of block copolymer-EPOcDNA formulations increased hematocrit in a dose-dependent manner for more than 9 months, without any initial overshoot. Low doses of block copolymer-EPOcDNA formulations prevented autoimmune anemia in immunocompetent Swiss mice and prevented or reversed chronic anemia in an acquired mouse model of renal failure. We conclude that repeated injections of low doses of block copolymer-DNA formulations that do not induce (1) inflammation at the injection site, (2) overexpression of EPO, or (3) the production of anti-EPO neutralizing auto-antibodies hold promise for in vivo expression of therapeutic proteins, in particular for systemic delivery.
Richard-Fiardo
Peggy
P
INSERM, U533, Nantes F-44035, France.
Payen
Emmanuel
E
Chèvre
Raphaël
R
Zuber
Julien
J
Letrou-Bonneval
Emilie
E
Beuzard
Yves
Y
Pitard
Bruno
B
D000740:Anemia / Q000139:chemically induced / Q000150:complications* / Q000235:genetics / Q000628:therapy*; D000818:Animals; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D015316:Genetic Therapy; D007249:Inflammation / Q000473:pathology; D007273:Injections, Intramuscular; D007668:Kidney / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics*; D011092:Polyethylene Glycols / Q000494:pharmacology; D051437:Renal Insufficiency / Q000150:complications*; D017701:Reticulocyte Count; D014508:Urea / Q000097:blood
C506200:Lutrol; D004921:Erythropoietin; D011092:Polyethylene Glycols; D014508:Urea; D003404:Creatinine