New therapeutics for primary hyperoxaluria type 1

Abstract

Purpose of review: Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that causes hepatic overproduction of oxalate and, often, nephrocalcinosis, nephrolithiasis, chronic kidney disease, and kidney failure. The purpose of the review is to provide an update on current emerging therapies for the treatment of PH1.

Recent findings: Use of ribonucleic acid interference (RNAi) therapeutics that target the liver to block production of key enzymes along pathways that generate oxalate is a promising approach. Available evidence supports the efficacy of both Lumasiran (targeting glycolate oxidase) and Nedosiran (targeting hepatic lactate dehydrogenase (LDHa)) to reduce urinary oxalate excretion in PH1. The efficacy of alternative approaches including stiripentol (an anticonvulsant drug that also targets LDHa), lanthanum (a potential gastrointestinal oxalate binder), and Oxalobacter formigenes (a bacterium that can degrade oxalate within the gastrointestinal tract and may also increase its secretion from blood) are all also under study. Genetic editing tools including clustered regularly interspaced short palindromic repeats/Cas9 are also in preclinical study as a potential PH1 therapeutic.

Summary: Novel treatments can reduce the plasma oxalate concentration and urinary oxalate excretion in PH1 patients. Thus, it is possible these approaches will reduce the need for combined kidney and liver transplantation to significantly decrease the morbidity and mortality of affected patients.

Figure 1.. Pathways leading to hepatic oxalate generation.

Glyoxylate is converted to glycine and pyruvate by alanine glyoxylate transferase enzyme (AGT) within peroxisomes. In primary hyperoxaluria type 1 (PH1), genetic variation of AGXT (encodes AGT) result in excess glyoxylate generation. Current evidence suggests that cytosolic lactate dehydrogenase isoform a (LDHa) converts glyoxylate to oxalate. Thus, agents that reduce LDHa activity can also potentially decrease oxalate generation in PH1 patients. Glycolate is a glyoxylate precursor generated by hepatic glycolate oxidase (GO). Therefore, agents that reduce hepatic GO activity can reduce glyoxylate and hence oxalate generation by affected patients with PH1. Variants in the gene that encodes glyoxylate reductase–hydroxypyruvate reductase (GRHPR) cause PH2, also due to increased intrahepatic glyoxylate generation. The exact mechanism whereby genetic variants in 4-hydroxy-2-oxoglutarate aldolase (HOGA), the cause of PH3, result in hyperoxaluria is currently unclear. Some evidence suggests that accumulation of the precursor 4-hydroxy-2-oxoglutarate inhibits GRHPR resulting in glyoxylate accumulation, that can then be converted to oxalate.