title: Inhibition of Glycolate Oxidase With Dicer-substrate siRNA Reduces Calcium Oxalate Deposition in a Mouse Model of Primary Hyperoxaluria Type 1.
abstract: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, metabolic disorder caused by mutations of alanine-glyoxylate aminotransferase (AGT), a key hepatic enzyme in the detoxification of glyoxylate arising from multiple normal metabolic pathways to glycine. Accumulation of glyoxylate, a precursor of oxalate, leads to the overproduction of oxalate in the liver, which accumulates to high levels in kidneys and urine. Crystalization of calcium oxalate (CaOx) in the kidney ultimately results in renal failure. Currently, the only treatment effective in reduction of oxalate production in patients who do not respond to high-dose vitamin B6 therapy is a combined liver/kidney transplant. We explored an alternative approach to prevent glyoxylate production using Dicer-substrate small interfering RNAs (DsiRNAs) targeting hydroxyacid oxidase 1 (HAO1) mRNA which encodes glycolate oxidase (GO), to reduce the hepatic conversion of glycolate to glyoxylate. This approach efficiently reduces GO mRNA and protein in the livers of mice and nonhuman primates. Reduction of hepatic GO leads to normalization of urine oxalate levels and reduces CaOx deposition in a preclinical mouse model of PH1. Our results support the use of DsiRNA to reduce liver GO levels as a potential therapeutic approach to treat PH1.
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Chaitali
authors.initials: C
authors.lastname: Dutta
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Avitahl-Curtis
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Pursell
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Marita
authors.initials: M
authors.lastname: Larsson Cohen
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Holmes
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Rohan
authors.initials: R
authors.lastname: Diwanji
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Luciano
authors.initials: L
authors.lastname: Apponi
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Koser
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Ying
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Dongyu
authors.initials: D
authors.lastname: Chen
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Shui
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Utsav
authors.initials: U
authors.lastname: Saxena
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Cyr
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Anee
authors.initials: A
authors.lastname: Shah
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Naim
authors.initials: N
authors.lastname: Nazef
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Wang
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Abrams
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Henryk
authors.initials: H
authors.lastname: Dudek
authors.affiliation: Instituto de Tecnologías Biomédicas (ITB), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Centre for Biomedical Research on Rare Diseases (CIBERER), Universidad La Laguna, Tenerife, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salido
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Bob D
authors.initials: BD
authors.lastname: Brown
authors.affiliation: Dicerna Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Chengjung
authors.initials: C
authors.lastname: Lai
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics*; D000818:Animals; D002129:Calcium Oxalate / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004195:Disease Models, Animal; D006038:Glyoxylates / Q000652:urine; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000201:enzymology / Q000628:therapy* / Q000652:urine; D008099:Liver / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology; D043244:Ribonuclease III / Q000378:metabolism
chemical_list: D006038:Glyoxylates; D034741:RNA, Small Interfering; D002129:Calcium Oxalate; D000429:Alcohol Oxidoreductases; C020821:glycollate oxidase; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; C031150:glyoxylic acid