Repurposing approved drugs as a pathway to novel treatments for Lafora Disease.

Lafora disease (LD) is a rare, fatal, progressive myoclonic epilepsy that leads to severe cognitive and motor deterioration. Symptoms typically appear in adolescence and life expectancy of affected individuals is about 10 years. LD is caused by mutations in the EPM2A or EPM2B genes, that encode for proteins laforin and malin, respectively – both of which are involved in regulating glycogen synthesis. Dysfunctions of these proteins lead to the accumulation of insoluble glycogen inclusions in the brain, known as Lafora bodies, which are primarily responsible for neurodegeneration (d'Orsi et al., Front. Neurol., 2022, 13). Currently, there is no therapy that can prevent glycogen accumulation or slow disease progression (Mitra et al., Rev Neurol., 2022, 178, 315-325). Available symptomatic treatments include antiseizure drugs, metformin, the ketogenic diet and trehalose (d'Orsi, Front Pharm., 2022). While enzyme- and oligonucleotide-based therapies are being explored, new therapeutic strategies are urgently needed. Recent studies suggest that SGLT2 inhibitors might offer a promising treatment option for LD (Imbrici et al., Pharmacol Res., 2024). Thus, identifying new pharmacological targets and drugs is crucial for developing early and effective treatments. In this respect, this This study aims to repurpose approved drugs by employing computational approaches, followed by validation through in vitro experiments. Methods Human glycogen synthase (hGYS1) and glucose transporters (GLUT1/3) have been selected as targets. Virtual screening, based on docking simulations, has been performed using 3D structures of hGYS1 and GLUT1/3 to identify potential drug candidates from the ChEMBL database. Drugs identified from the in silico screening will be tested in SHSY-5Y cells for their ability to modulate intracellular glucose and glycogen concentration using specific in vitro assays. Results Computational screening identified several promising drug candidates, including zoledronic acid, canagliflozin and nebivolol, as potential binders to the selected targets. In vitro validation assays are currently ongoing. Conclusion This study successfully identified approved drugs able to modulate glucose concentration. This integrated research strategy based on the repurposing of commercial drugs could accelerate the discovery of new therapies for LD.