RNA-based rescue of inhibition as potential treatment for genetic GABRA1-dependent epilepsy

A broad spectrum of genetic epilepsies is linked to mutations in the GABRA1 gene, which encodes the α1 subunit of GABAA receptors, a major player in mediating inhibitory signals in the brain. GABRA1 mutations lead to a loss-of-function of brain inhibition mediated by GABAA receptors, thus potentially resulting in epileptic seizures. As such, a logical therapeutic intervention would be to enhance the expression of α1 in individuals carrying GABRA1 mutations to restore inhibition and revert the epileptic phenotype. This project will pursue this therapeutic avenue by exploiting SINEUP technology, which are RNA molecules able to increase the expression of any specific target gene. We previous identified specific SINEUPs that can increase α1 protein (SINEUP-GABRA1). In this pre-clinical project, we will validate SINEUP-GABRA1 as an effective strategy to ameliorate GABRA1-dependent epilepsy. To pursue this objective, we will first take advantage of an epileptic mutant mouse that has deficient α1 expression. In this animal model, we will assess if SINEUP-GABRA1 can i) restore inhibitory signals and ii) suppress epileptic seizures. Second, we will test whether SINEUP-GABRA1 can suppress epileptic-like activity in neurons differentiated from dermal cells of epileptic patients. The successful validation of SINEUP-GABRA1 in both animal and human models will move us towards a novel, versatile and personalized RNA therapy for the cure of several types of epilepsy. This work will yield the greatest benefit for patients affected by devastating forms of epileptic encephalopathies that current available treatments leave behind.