An investigational RNAi therapeutic targeting glycolate oxidase reduces oxalate production in models of primary hyperoxaluria

Academic Article


  • Primary hyperoxaluria type 1 (PH1), an inherited rare disease of glyoxylatemetabolism, arises frommutations 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 patientsmanages the disease with vitamin B6 treatments, the only effective treatment formost 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 inwild-type mice, rats, and nonhuman primates. ALNGO1 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 geneticmouse model of PH1, and up to 98%after multiple doses in a ratmodel of hyperoxaluria. These data demonstrate the ability ofALN-GO1to reduce oxalate production in preclinicalmodels ofPH1 acrossmultiple species and provide a clear rationale for clinical trials with this compound.
  • Authors

    Digital Object Identifier (doi)

    Pubmed Id

  • 23896047
  • Author List

  • Liebow A; Li X; Racie T; Hettinger J; Bettencourt BR; Najafian N; Haslett P; Fitzgerald K; Holmes RP; Erbe D
  • Start Page

  • 494
  • End Page

  • 503
  • Volume

  • 28
  • Issue

  • 2