Advances in the design and discovery of novel small molecule drugs for the treatment of Dravet Syndrome

Introduction: Dravet syndrome (severe myoclonic epilepsy in infancy) begins in the first year of life characterized by generalized or unilateral clonic seizures that are frequently triggered by high fever. A subsequent worsening stage occurs (in years 1-4 of life) and seizure activity is accompanied by disturbed psychomotor development. The third stage of the disease, known as the 'stabilization phase,' is associated with seizures and intellectual impairment. Of note, a mutation in the voltage-gated sodium-channel gene alpha 1 subunit (SCN1A) has been found in around 85% of patients with Dravet syndrome. Areas covered: The authors review the current treatment strategies as well as potential drugs in the initial stages of clinical evaluation. The authors also review drugs with protective activity in mice models of Dravet syndrome. Expert opinion: Experimental data and results from initial clinical studies have brought attention to several drugs with various mechanisms of action including: ataluren (a suppressant of premature stop codons; under clinical evaluation), EPX-100, EPX-200, fenfluramine (serotonin modulators), soticlestat (an 24-hydroxylase cholesterol enzyme inhibitor), SPN-817 (an inhibitor of acetylcholinesterase), verapamil (a voltage-dependent calcium channel inhibitor) and STK-001 (an antisense oligonucleotide). The latter is scheduled for clinical evaluation.