Pediatrics

Biography

Biography: Shinichi Hirose

Abstract

While induced pluripotent stem cells (iPSCs) are generally considered to be used in regenerative medicine, they can also be used to reproduce disease pathophysiology in vitro. This ability to replicate disease pathophysiology using iPSCs may be beneficial for intractable childhood disorders, specifically those involving the central nervous system, such as Dravet Syndrome. Dravet Syndrome, one of the intractable genetic epilepsies affecting children, is caused by mutations of SCN1A, the gene encoding the α1 subunit of Na⁺ channels in the brain. To understand the pathomechanisms of Dravet Syndrome, we established iPSC lines from a patient harboring a pathological SCN1A mutation and differentiated the iPSCs into neuronal cells. We found, for the first time in humans, that the derived inhibitory GABAergic neurons had impaired action potentials compared to neurons derived from control iPSC lines. This finding is consistent with results from genetically engineered murine models with Scn1a mutations. Thus, the pathomechanisms of Dravet Syndrome can be attributed to dysfunction of the inhibitory interneurons, termed interneuronopathy, due to SCN1A mutations. The discovery of these molecular pathomechanisms aligns with clinical observations that some anti-epileptic drugs that block Na⁺ channels precipitate seizures in patients with Dravet Syndrome. This new understanding of the pathomechanisms of Dravet Syndrome should open fresh avenues for novel drug development. Additionally, current technologies are able to readily introduce any mutation into iPSCs, which can facilitate high-throughput iPSC screening platforms for new potential drugs that target affected organs, even in rare genetic intractable childhood disorders.