Histology and distribution of virally-delivered eEF1A2 (360G-Wellcome-211391_Z_18_Z)

Childhood epilepsy affects 1 in 200 children with 20% of affected children being unresponsive to available currently medical treatments resulting in significant health morbidity and socioeconomic cost. Genetic causes of epilepsy are increasing recognised with genome sequencing, resulting in further understanding of disease mechanisms. Mutations in the Eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) gene has recently been identified to cause early onset epileptic encephalopathy and intellectual disability. These children suffer medically refractory epilepsy with significant neurodisability and there is clear medical need to develop new treatments for these children. The success of adeno-associated virus (AAV) mediated gene therapy in spinal muscular atrophy and several neurometabolic syndromes provide compelling clinical precedents to develop gene therapy for genetic epilepsies such as EEF1A2 related childhood neurological disease. Professor Schorge's translational neuroscience research group has developed gene therapies for epilepsy towards clinical trial already and we hypothesise that eEF1A2 neuronal function can be restored by AAV9 mediated gene transfer. We will use the EEF1A2 null mouse that has reduced survival to 23 days with vacuolar degeneration in the spinal cord. We will deliver AAV EEF1A2 gene therapy to EEF1A2 null mouse model and evaluate vector biodistribution and effects on nervous system histology.