Hepatic Lactate Dehydrogenase A: An RNA Interference Target for the Treatment of All Known Types of Primary Hyperoxaluria.

INTRODUCTION

Primary hyperoxaluria (PH) is a family of 3 rare genetic disorders of hepatic glyoxylate metabolism that lead to overproduction and increased renal excretion of oxalate resulting in progressive renal damage. inhibition of glyoxylate-to-oxalate conversion by RNA interference (RNAi) has emerged as a potential therapeutic option for all types of PH. is mainly expressed in the liver and muscles.

METHODS

Nonclinical data in mice and nonhuman primates show that inhibition by RNAi reduces urinary oxalate excretion and that its effects are liver-specific without an impact on off-target tissues, such as the muscles. To confirm the lack of unintended effects in humans, we analyzed data from the phase I randomized controlled trial of single-dose nedosiran, an RNAi therapy targeting hepatic . We conducted a review of the literature on LDHA deficiency in humans, which we used as a baseline to assess the effect of hepatic inhibition.

RESULTS

Based on a literature review of human LDHA deficiency, we defined the phenotype as mainly muscle-related with no liver manifestations. Healthy volunteers treated with nedosiran experienced no drug-related musculoskeletal adverse events. There were no significant alterations in plasma lactate, pyruvate, or creatine kinase levels in the nedosiran group compared with the placebo group, signaling the uninterrupted interconversion of lactate and pyruvate and normal muscle function.

CONCLUSION

Phase I clinical data on nedosiran and published nonclinical data together provide substantial evidence that inhibition is a safe therapeutic mechanism for the treatment of all known types of PH.