Improving Treatment Options for Primary Hyperoxaluria

Abstract

The primary hyperoxalurias are three rare inborn errors of the glyoxylate metabolism in the liver, which lead to massively increased endogenous oxalate production, thus elevating urinary oxalate excretion and, based on that, recurrent urolithiasis and/or progressive nephrocalcinosis. Frequently, especially in type 1 primary hyperoxaluria, early end-stage renal failure occurs. Treatment possibilities are scare, namely, hyperhydration and alkaline citrate medication. In type 1 primary hyperoxaluria, vitamin B₆, though, is helpful in patients with specific missense or mistargeting mutations. In those vitamin B₆ responsive, urinary oxalate excretion and concomitantly urinary glycolate is significantly decreased, or even normalized. In patients non-responsive to vitamin B₆, RNA interference medication is now available. Lumasiran^® is already available on prescription and targets the messenger RNA of glycolate oxidase, thus blocking the conversion of glycolate into glyoxylate, hence decreasing oxalate, but increasing glycolate production. Nedosiran blocks liver-specific lactate dehydrogenase A and thus the final step of oxalate production. Similar to vitamin B₆ treatment, where both RNA interference urinary oxalate excretion can be (near) normalized and plasma oxalate decreases, however, urinary and plasma glycolate increases with lumasiran treatment. Future treatment possibilities are on the horizon, for example, substrate reduction therapy with small molecules or gene editing, induced pluripotent stem cell-derived autologous hepatocyte-like cell transplantation, or gene therapy with newly developed vector technologies. This review provides an overview of current and especially new and future treatment options.

Fig. 1

Glyoxylate metabolic pathway in the liver (modified from Martin-Higueras et al. [7]). The enzymatic deficits responsible for the three known types of primary hyperoxaluria are shown (I, II, and III). Oxalate is then secreted out of the liver, to be excreted by the kidneys. High levels of oxalate in the kidneys and urine lead to formation of calcium oxalate (CaOx) in the renal tissue and tubular system, causing urolithiasis (upper image) and/or nephrocalcinosis (lower image), which can be detected by ultrasound imaging procedures. 1P5CDH Δ1-pyrroline-5-carboxylate dehydrogenase, AGT alanine:glyoxylate aminotransferase, AspAT aspartate aminotransferase, DAO D-aminoacid oxidase, GO glycolate oxidase, GRHPR glyoxylate reductase/hydropyruvate reductase, HOGA 4-hydroxy-2- oxoglutarate aldolase 1, HYPDH hydroxyproline dehydrogenase, LDH L-lactate dehydrogenase

Fig. 2

Schematic of treatment for patients with primary hyperoxaluria (PH). If diagnosis is suspected, all patients with PH must be given the standard treatment of care by means of hyperhydration and citrate medication. In addition, patients with PH type 1 (PH1) should receive vitamin B₆ (Vit B6) until a genetic diagnosis is available. With a genetic diagnosis in hand, the therapeutical processes are depicted in the figure. AKF acute kidney failure, ESKD end-stage kidney failure, PH2 PH type 2, PH3 PH type 3, RNAi RNA interference, Tx transplantation. *Missense mutations that respond to VitB6: p.G170R, p.G41R, p.F152I

Fig. 3

Strategies for molecular therapy in primary hyperoxaluria (updated from Martin-Higueras et al. [7]): gene therapy with single-stranded adeno-associated virus (ssAAV) carrying one copy of AGXT cDNA (here also applicable SV40 as a vehicle); cell therapy by hepatocyte transplantation, including the potential autologous transplantation of human induced pluripotent stem cell-derived hepatocytes; proteostasis regulation therapy targeting molecular chaperones (Hsp60 and Hsp90) such as dequalinium chloride, monesin, and emetine, or directly stabilizing the (AGT) enzyme with the cofactor pyridoxine (B6); enzyme replacement therapy (ERT) by delivery of polymer-conjugated AGT proteins into the peroxisomal compartment; and substrate reduction therapy (SRT) through inhibition of glycolate oxidase (GO) in the peroxisome and/or lactate dehydrogenase A (LDHA) in the cytosol either by RNA interference or by small molecules, or by editing the corresponding gene. AGT alanine:glyoxylate aminotransferase, responsible for PH1, AGT-Mi AGT in the minor haplotype, DAO D-amino acid oxidase, GRHPR glyoxylate reductase/hydroxypyruvate reductase, enzyme deficient in PH2, HOGA1 4-hydroxy-2-oxoglutarate aldolase 1, involved in PH3, LDH L-lactate dehydrogenase