Epilepsy linked toTBC1D24 Loss: pH-Targeted Pharmacological and Nanotechnological Interventions

Awardee: Caterina Michetti

Institution: University of Genoa

Grant Amount: $62,937

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

This project aims to exploit a new preclinical mouse model (Tbc1d24-cKO) to study early-onset epilepsy caused by TBC1D24 loss. Using this model, we will test two innovative treatment strategies targeting the root causes of hyperexcitability in neurons. The first approach involves a small molecule that enhances lysosomal acidification by stimulating the v-ATPase enzyme, restoring pH balance in neuronal cells and potentially reducing neuronal hyperactivity. The second approach involves a novel nanomachine called pHIL, which is designed to selectively inhibit overactive neurons in response to pH shifts that occur during seizures. By activating a light-sensitive protein under acidic conditions, pHIL can reduce excitability without affecting healthy neurons. This research is particularly relevant to early-onset epilepsy linked to TBC1D24 pathogenic variants, a condition with no effective treatments. Our Tbc1d24-cKO mouse model allows us to test these therapies in vivo, offering a unique opportunity to explore the underlying mechanisms of epileptogenesis and to identify robust therapeutic strategies. The proposed strategies target different aspects of the pH imbalance associated with TBC1D24 loss, and testing both approaches improves the likelihood of finding an effective treatment for early-onset epilepsy.