Targeting the polyamine metabolism to treat pharmacoresistant epilepsy

• Applicants: Professor Dr. Heinz Beck; Dr. Karen Van Loo
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 571322729

More than 65 million people worldwide are affected by epilepsy. In ~30% of these patients (approx. 20 million), seizures are not controlled by available antiseizure drugs (ASDs), with considerable personal and socio-economic consequences. We have now discovered a cell biological mechanism of pharmacoresistance, which is based on a disruption of polyamine metabolism, and an entirely novel interaction of intracellular polyamines and ASDs at voltage-gated sodium channels. Specifically, our preliminary data shows that in chronic experimental epilepsy, transcriptional regulation of enzymes of the polyamine metabolism substantially modifies the polyamine landscape in hippocampal cells. The regulation of two enzymes, spermine synthase (SMS) and spermine/spermidine N1-acetyltransferase (SSAT) likely work together to generate high levels of N1-acetylspermidine. This polyamine severely impairs the ability of common ASDs to induce use-dependent sodium channel block, a key anticonvulsant mechanism. In this proposal, we will examine the mechanisms of transcriptional regulation for SMS and SSAT using in-silico and molecular biological approaches (Aim 1). We will then develop inducible, CRISPR-based approaches to normalize expression of SMS and SSAT, and study if this corrects epilepsy-associated changes in polyamine metabolism, recovers sensitivity of sodium channels to ASDs in-vitro, and reinstates ASD sensitivity of seizures in-vivo (Aims 2 and 3). In the case of SSAT, we have identified an existing small molecule that is already used in patients for other indications, that has been identified as a potent SSAT inhibitor. We will test if this compound can reinstate CBZ responses in epileptic mice (Aim 4). Finally, we will leverage human organotypic cultures to study if either rescuing SMS expression or inhibiting SSAT expression improves response to ASDs in a human system. These results address a long-standing clinical problem with an unmet medical need, and leverage a novel mechanism underlying pharmacoresistance to generate novel treatment options for chronic epilepsy.

• DFG Programme: Research Grants