title: Treatment of erythropoietin deficiency in mice with systemically administered siRNA.
abstract: Anemia linked to a relative deficiency of renal erythropoietin production is a significant cause of morbidity and medical expenditures in the developed world. Recombinant erythropoietin is expensive and has been linked to excess cardiovascular events. Moreover, some patients become refractory to erythropoietin because of increased production of factors such as hepcidin. During fetal life, the liver, rather than the kidney, is the major source of erythropoietin. In the present study, we show that it is feasible to reactivate hepatic erythropoietin production and suppress hepcidin levels using systemically delivered siRNAs targeting the EglN prolyl hydroxylases specifically in the liver, leading to improved RBC production in models of anemia caused by either renal insufficiency or chronic inflammation with enhanced hepcidin production.
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA 02215, USA. william_kaelin@dfci.harvard.edu
authors.forename: William
authors.initials: W
authors.lastname: Querbes
authors.forename: Roman L
authors.initials: RL
authors.lastname: Bogorad
authors.forename: Javid
authors.initials: J
authors.lastname: Moslehi
authors.forename: Jamie
authors.initials: J
authors.lastname: Wong
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Chan
authors.forename: Elena
authors.initials: E
authors.lastname: Bulgakova
authors.forename: Satya
authors.initials: S
authors.lastname: Kuchimanchi
authors.forename: Akin
authors.initials: A
authors.lastname: Akinc
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
mesh_terms: D000740:Anemia / Q000209:etiology / Q000235:genetics / Q000628:therapy; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D004920:Erythropoiesis / Q000235:genetics; D004921:Erythropoietin / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D005240:Feasibility Studies; D005260:Female; D064451:Hepcidins; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007249:Inflammation / Q000150:complications; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D051437:Renal Insufficiency / Q000150:complications
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D034741:RNA, Small Interfering; D004921:Erythropoietin; C522721:PHD1 protein, mouse; C522722:PHD3 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases