Lactate dehydrogenase 5: identification of a druggable target to reduce oxaluria

Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias

“…The strategy of drug repurposing [ 227 ] has afforded a possible new indication for an already marketed anticonvulsant drug. Stiripentol highlights the suitability of a small molecule LDHA inhibitor for PH1 treatment [ 53 , 57 ], after it was noticed that patients receiving stiripentol had a lower urine oxalate excretion. Though a significant reduction of urine oxalate excretion was attained after one PH1 patient received stiripentol [ 57 ], this drug failed to lower the plasma oxalate concentration in a PH patient with advanced chronic kidney disease [ 167 ].…”

“…Another possibility is the prevention of oxalate formation by direct inhibition/silencing of the enzyme in charge of its formation from the accumulated glyoxylate, the hepatic isozyme LDHA ( Figure 1 ) [ 53 , 54 ]. Following this strategy, useful therapeutic agents might be found against the three types of PHs.…”

Investigational Therapies for Primary Hyperoxaluria

“…While being indicative of hepatic LDH inhibitory activity in humans, it is unclear how comparable the cystinuria group was to healthy control subjects, with regard to baseline urinary oxalate levels. In a case study, stiripentol treatment at 50 mg/kg/day in a PH patient, representing the upper recommended dose limit in Dravet syndrome, could also reduce urinary oxalate to below 50% compared to before treatment, without signs of side effects, further suggesting potential activity of this drug in humans (Figure ).…”

“…More clarity about the efficacy of stiripentol in the treatment of PH will be gained by a currently enrolling phase II clinical study (). While small molecule LDH inhibitors might provide an alternative to siRNA based silencing, stiripentol is associated with important side effects, such as loss of appetite, sleep disturbance, ataxia, hyperactivity/irritability, and neutropenia, which might limit its application. , Additionally, it undergoes hepatic metabolism, and interacts with CYP1A2, CYP2B6, and CYP3A4; thus, drug–drug interactions need to be considered . Stiripentol has relatively low affinity for LDH5, but the forthcoming clinical trial could raise further interest in developing more potent and safer LDH5 inhibitors.…”

“…Further, an interesting drug repurposing study targeting LDH5, the LDH isoenzyme expressed in the liver, 45 was published by Le Dudal and co-workers in 2019. 30 In this work, they evaluated the potential application of stiripentol, a LDH5 inhibitor used in the treatment of Dravet syndrome, a type of epilepsy, 46 to reduce hepatic oxalate production.…”