title: A single dose of EGLN1 siRNA yields increased erythropoiesis in nonhuman primates.
abstract: Decreased production of erythropoietin (EPO) causes anemia in patients with chronic kidney disease, and recombinant human EPO is used to treat renal failure associated anemia. The liver, the main EPO-producing organ in utero, maintains the capacity to produce EPO in the adult but in insufficient quantities to restore hemoglobin levels to normal in patients with impaired renal function. Inhibition of prolyl-4-hydroxylase domain (PHD) proteins is known to cause an increase in EPO production through its effects on hypoxia inducible factor. Here, we utilized small interfering RNA (siRNA) targeting EGLN1, the gene encoding the PHD2 protein, to investigate the phenotypic consequences in nonhuman primates. A single, well-tolerated intravenous dose of an optimized EGLN1 siRNA encapsulated in a lipid nanoparticle formulation caused robust mRNA silencing in the liver, leading to increases in serum EPO and hemoglobin. The siRNA-induced erythropoiesis was dose-dependent and was sustained for at least 2 months. These data point to the potential for an RNA interference-based, liver-targeted therapeutic approach for the treatment of anemia.
authors.affiliation: 1 Merck Research Laboratories , West Point, Pennsylvania.
authors.forename: Marc T
authors.initials: MT
authors.lastname: Abrams
authors.forename: Martin
authors.initials: M
authors.lastname: Koser
authors.forename: Julja
authors.initials: J
authors.lastname: Burchard
authors.forename: Walter
authors.initials: W
authors.lastname: Strapps
authors.forename: Huseyin
authors.initials: H
authors.lastname: Mehmet
authors.forename: Marian
authors.initials: M
authors.lastname: Gindy
authors.forename: Dennis
authors.initials: D
authors.lastname: Zaller
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.forename: Dominique
authors.initials: D
authors.lastname: Stickens
mesh_terms: D000818:Animals; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D008099:Liver / Q000187:drug effects; D008253:Macaca mulatta; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D034741:RNA, Small Interfering; D004921:Erythropoietin; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases