title: An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria.
abstract: Primary hyperoxaluria type 1 (PH1), an inherited rare disease of glyoxylate metabolism, arises from mutations in the enzyme alanine-glyoxylate aminotransferase. The resulting deficiency in this enzyme leads to abnormally high oxalate production resulting in calcium oxalate crystal formation and deposition in the kidney and many other tissues, with systemic oxalosis and ESRD being a common outcome. Although a small subset of patients manages the disease with vitamin B6 treatments, the only effective treatment for most is a combined liver-kidney transplant, which requires life-long immune suppression and carries significant mortality risk. In this report, we discuss the development of ALN-GO1, an investigational RNA interference (RNAi) therapeutic targeting glycolate oxidase, to deplete the substrate for oxalate synthesis. Subcutaneous administration of ALN-GO1 resulted in potent, dose-dependent, and durable silencing of the mRNA encoding glycolate oxidase and increased serum glycolate concentrations in wild-type mice, rats, and nonhuman primates. ALN-GO1 also increased urinary glycolate concentrations in normal nonhuman primates and in a genetic mouse model of PH1. Notably, ALN-GO1 reduced urinary oxalate concentration up to 50% after a single dose in the genetic mouse model of PH1, and up to 98% after multiple doses in a rat model of hyperoxaluria. These data demonstrate the ability of ALN-GO1 to reduce oxalate production in preclinical models of PH1 across multiple species and provide a clear rationale for clinical trials with this compound.
authors.affiliation: Alnylam Pharmaceuticals, Departments of Research and Development, Cambridge, Massachusetts; and aliebow@alnylam.com.
authors.forename: Abigail
authors.initials: A
authors.lastname: Liebow
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Xingsheng
authors.initials: X
authors.lastname: Li
authors.affiliation: Alnylam Pharmaceuticals, Departments of Research and Development, Cambridge, Massachusetts; and.
authors.forename: Timothy
authors.initials: T
authors.lastname: Racie
authors.affiliation: Alnylam Pharmaceuticals, Departments of Research and Development, Cambridge, Massachusetts; and.
authors.forename: Julia
authors.initials: J
authors.lastname: Hettinger
authors.affiliation: Alnylam Pharmaceuticals, Departments of Research and Development, Cambridge, Massachusetts; and.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bettencourt
authors.affiliation: Alnylam Pharmaceuticals, Departments of Research and Development, Cambridge, Massachusetts; and.
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
authors.affiliation: Alnylam Pharmaceuticals, Departments of Research and Development, Cambridge, Massachusetts; and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Haslett
authors.affiliation: Alnylam Pharmaceuticals, Departments of Research and Development, Cambridge, Massachusetts; and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Ross P
authors.initials: RP
authors.lastname: Holmes
authors.affiliation: Alnylam Pharmaceuticals, Departments of Research and Development, Cambridge, Massachusetts; and.
authors.forename: David
authors.initials: D
authors.lastname: Erbe
authors.affiliation: Alnylam Pharmaceuticals, Departments of Research and Development, Cambridge, Massachusetts; and.
authors.forename: William
authors.initials: W
authors.lastname: Querbes
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: John
authors.initials: J
authors.lastname: Knight
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D020868:Gene Silencing; D006960:Hyperoxaluria, Primary / Q000201:enzymology* / Q000628:therapy*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D010070:Oxalates / Q000378:metabolism*; D011323:Primates; D012333:RNA, Messenger; D000067492:RNAi Therapeutics; D051381:Rats
chemical_list: D010070:Oxalates; D012333:RNA, Messenger; D000429:Alcohol Oxidoreductases; C020821:glycollate oxidase
keywords: RNAi therapeutics; end-stage renal disease; oxalate; primary hyperoxaluria type I; siRNA