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

Abstract

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. LDHA inhibition of glyoxylate-to-oxalate conversion by RNA interference (RNAi) has emerged as a potential therapeutic option for all types of PH. LDHA is mainly expressed in the liver and muscles.

Methods: Nonclinical data in mice and nonhuman primates show that LDHA 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 LDHA. We conducted a review of the literature on LDHA deficiency in humans, which we used as a baseline to assess the effect of hepatic LDHA 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 LDHA inhibition is a safe therapeutic mechanism for the treatment of all known types of PH.

Keywords: RNA interference; lactate dehydrogenase A; nedosiran; primary hyperoxaluria; small interfering RNA.

Graphical abstract

Figure 1

Glyoxylate metabolism in primary hyperoxaluria. Lactate dehydrogenase (LDH)–mediated conversion of glyoxylate to oxalate in the liver is the ultimate step resulting in oxalate overproduction in primary hyperoxaluria types 1, 2, and 3. Nedosiran is an investigational RNA interference therapy designed to inhibit hepatic LDH (encoded by LDHA). AGT, alanine:glyoxylate aminotransferase; GO, glycolate oxidase; GRHPR, glyoxylate reductase/hydroxypyruvate reductase; HOG, 4-hydroxy-2-oxoglutarate; HOGA, 4-hydroxy-2-oxoglutarate aldolase.

Figure 2

Patients with lactate dehydrogenase A (LDHA) deficiency: symptoms reported in the published literature. The symptoms of LDHA deficiency reported for the 14 patients were primarily muscle-related (green bars). Multiple symptoms were reported in a single patient in some cases.

Figure 3

Plasma lactate distribution in healthy volunteers. Scatter plot showing plasma lactate levels in healthy volunteers at baseline (day 0) and at the end of the study (day 29) in placebo and nedosiran groups. Inset graph (in gray) shows plasma lactate distribution by nedosiran dose. SD, standard deviation

Figure 4

Plasma pyruvate distribution in healthy volunteers. Scatter plot showing plasma pyruvate levels in healthy volunteers at baseline (day 0) and at the end of the study (day 29) in placebo and nedosiran groups. Inset graph (in gray) shows plasma pyruvate distribution by nedosiran dose. SD, standard deviation.

Figure 5

Plasma creatine kinase (CK) distribution in healthy volunteers. Scatter plot showing plasma CK levels in healthy volunteers at baseline (day 0) and at the end of the study (day 29) in placebo and nedosiran groups. Inset graph (in gray) shows plasma CK distribution by nedosiran dose. SD, standard deviation.

Figure 6

Superimposed lactate, pyruvate, and creatine kinase (CK) distribution profiles in healthy volunteers. Superimposed scatter plots showing (a) lactate, (b) pyruvate, and (c) CK profiles in the nedosiran (N = 15) and placebo (N = 10) groups at timepoints between days 0 and 29 (days 2, 8, 15, and 22). One participant had a missing lactate value, and another participant had a missing pyruvate value, both on day 2 within the placebo group. SD, standard deviation.