title: Human erythropoietin gene delivery using an arginine-grafted bioreducible polymer system.
abstract: Erythropoiesis-stimulating agents are widely used to treat anemia for chronic kidney disease (CKD) and cancer, however, several clinical limitations impede their effectiveness. Nonviral gene therapy systems are a novel solution to these problems as they provide stable and low immunogenic protein expression levels. Here, we show the application of an arginine-grafted bioreducible poly(disulfide amine) (ABP) polymer gene delivery system as a platform for in vivo transfer of human erythropoietin plasmid DNA (phEPO) to produce long-term, therapeutic erythropoiesis. A single systemic injection of phEPO/ABP polyplex led to higher hematocrit levels over a 60-day period accompanied with reticulocytosis and high hEPO protein expression. In addition, we found that the distinct temporal and spatial distribution of phEPO/ABP polyplexes contributed to increased erythropoietic effects compared to those of traditional EPO therapies. Overall, our study suggests that ABP polymer-based gene therapy provides a promising clinical strategy to reach effective therapeutic levels of hEPO gene.
authors.affiliation: Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112-5820, USA.
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Lee
authors.forename: Hye Yeong
authors.initials: HY
authors.lastname: Nam
authors.forename: Jaesung
authors.initials: J
authors.lastname: Kim
authors.forename: Minhyung
authors.initials: M
authors.lastname: Lee
authors.forename: James W
authors.initials: JW
authors.lastname: Yockman
authors.forename: Sug Kyun
authors.initials: SK
authors.lastname: Shin
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000740:Anemia / Q000628:therapy*; D000818:Animals; D001120:Arginine; D004247:DNA / Q000235:genetics; D004912:Erythrocytes / Q000378:metabolism; D004920:Erythropoiesis; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006400:Hematocrit; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D053758:Nanoparticles; D011073:Polyamines; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D045262:Reticulocytosis; D014162:Transfection
chemical_list: D011073:Polyamines; D012333:RNA, Messenger; C534803:arginine-grafted bioreducible poly(disulfide amine)polymer; D004921:Erythropoietin; D004247:DNA; D001120:Arginine