Clioquinol as a new therapy in epilepsy: From preclinical evidence to a proof-of-concept clinical study.

OBJECTIVE

Drug-resistant epilepsy (DRE) affects >25 million people worldwide and is often associated with neuroinflammation. Increasing evidence links deficiency or malfunctioning of the enzyme phosphoglycerate dehydrogenase (PHGDH), which converts 3-phosphoglycerate to generate serine and the neurotransmitter glycine, with (drug-resistant) epilepsy. Moreover, PHGDH, which is primarily expressed in astrocytes within the brain, has been identified as a critical enzyme in driving macrophage polarization toward an anti-inflammatory state. Hence, PHGDH activators may be beneficial for treating DRE by exhibiting both antiseizure and anti-inflammatory activity. The objective of this study was to identify such PHGDH activators.

METHODS

We screened a drug repurposing library for PHGDH activators and assessed their antiseizure and anti-inflammatory properties using various zebrafish and mouse epilepsy models and explored the mechanistic consequences of activating PHGDH in a cell line, in astrocytes, and in zebrafish heads. Finally, we assessed the efficacy of clioquinol as add-on treatment in three severe DRE patients in a clinical open pilot proof-of-concept study.

RESULTS

We identified haloquinolines from a drug repurposing library as potent activators of PHGDH. The most promising haloquinoline clioquinol can increase the catalytic activity of PHGDH up to 2.5-fold, thereby increasing de novo glycine biosynthesis and resulting in reduced glutamate levels. Moreover, we show that clioquinol has PHGDH-dependent antiseizure activity as well as anti-inflammatory properties in vivo using various zebrafish and mouse epilepsy models. Finally, we demonstrate the efficacy of clioquinol as add-on treatment in severe DRE patients; two patients showed a 37%-47% reduction in seizure frequency, and all three patients noted a positive impact on quality of life and seizure severity.

SIGNIFICANCE: Increasing activity of PHGDH is a promising new approach to treat DRE.