SiRNA Therapeutics for Primary Hyperoxaluria: A Beginning

Abstract

Realization of the early promise of gene therapy has been elusive. Long and eagerly anticipated, particularly for orphan diseases with few available therapeutic alternatives, only within recent years have such treatments begun to reach phase III clinical trials.1 Two articles in this issue of Molecular Therapy identify inhibition of glycolate oxidase as a potential treatment for type 1 primary hyperoxaluria (PH1), an autosomal recessive condition in which excess oxalate produced by the liver causes kidney damage and severe systemic disease. Both teams of investigators demonstrated reduction in oxalate production in a mouse knockout model of the disease through absence or inhibition of glycolate oxidase (GO). Hepatic GO converts glycolate to glyoxylate, which is the primary substrate for production of oxalate. Thus, substrate reduction was achieved. Martin-Higueras and colleagues2 demonstrated that the hyperoxaluria of the AGXT knockout mouse was substantially reduced following double knockout of AGXT and GO. Dutta and colleagues3 approached the problem differently, using Dicer-short interfering RNA (Dicer-siRNA) for inhibition targeting hydroxyacid oxidase 1 (HAO-1) messenger RNA, which encodes GO.3 Using this approach, they were able to demonstrate normalization of oxalate production in hepatocytes of AGXT knockout mice. These observations suggest an innovative approach to treatment for patients with PH1 and impart new hope for patients with PH, their families, and the physicians who care for them. This is especially true in that early experience with other applications of siRNA for treatment of human diseases, including amyloidosis, hypercholesterolemia, and α1-antitrypsin deficiency, has been encouraging.1,4