A novel promising therapeutic paradigm in a preclinical mouse model for developmental and epileptic encephalopathy

Developmental and epileptic encephalopathies (DEE) are severe forms of early onset epilepsies with drug-resistant seizures, global developmental delay and intellectual disability. One of the monogenic causes of DEE are expansion mutations in a GCN codon repeat of the Aristaless related homeobox (ARX) gene that lead to a polyalanine (polyAla) elongation. Here we report on the epilepsy behaviour analysis of the preclinical mouse model of DEE, Arx polyAla that express the c.330ins(GCG)7 mutation through the insertion of seven GCG alanine codons in the first polyAla stretch. These mice exhibit severe spontaneous tonic-clonic seizures and present a high risk for SUDEP. We present promising data on in vivo post-natal treatments with the Food-Drug Administration (FDA)-approved HDAC inhibitor Vorinostat, which anticonvulsant property has been widely reported. The treatment was done by daily intraperitoneal injection for 7 days, after quantification of baseline seizure frequency. By continuous video-recording, we quantified the severity of different stages of spontaneous convulsive seizures (Racine stages 3-5). Reduced epilepsy frequency and slightly improvement of the phenotype severity were observed in a pilot number of Arx polyAla animals. Importantly, we found that Vorinostat treatment offset molecular processes damaged in the Arx polyAla cortex. Although further studies are indispensable to define the global impact of Vorinostat activity, these results pave the way for the design of novel therapeutic interventions for ARX pharmaco-resistant epilepsy and other early-onset genetic epilepsies.