An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria
Open Access
- 18 July 2016
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 28 (2), 494-503
- https://doi.org/10.1681/asn.2016030338
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.Keywords
This publication has 31 references indexed in Scilit:
- Safety and Efficacy of RNAi Therapy for Transthyretin AmyloidosisThe New England Journal of Medicine, 2013
- Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo**Angewandte Chemie-International Edition, 2012
- High resolution crystal structure of rat long chain hydroxy acid oxidase in complex with the inhibitor 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1, 2, 3-thiadiazole. Implications for inhibitor specificity and drug designBiochimie, 2012
- Hydroxyproline metabolism in mouse models of primary hyperoxaluriaAmerican Journal of Physiology-Renal Physiology, 2012
- A status report on RNAi therapeuticsSilence, 2010
- Targeted Delivery of RNAi Therapeutics With Endogenous and Exogenous Ligand-Based MechanismsMolecular Therapy, 2010
- Active Site and Loop 4 Movements within Human Glycolate Oxidase: Implications for Substrate Specificity and Drug DesignBiochemistry, 2008
- Alanine–glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transferProceedings of the National Academy of Sciences of the United States of America, 2006
- Glycolate and glyoxylate metabolism in HepG2 cellsAmerican Journal of Physiology-Cell Physiology, 2004
- End-stage renal disease of the Tunisian child: epidemiology, etiologies, and outcomePediatric Nephrology, 1996