Reprogramming somatic cells to a pluripotent state via the induced pluripotent stem cell (iPSC) method offers an unparalleled approach for neurological disease modeling using patient-derived neurons.
My laboratory has applied the iPSC approach in combination with genetically modified mice to model severe childhood genetic early infantile epileptic encephalopathies (EIEEs) with patient-derived cells. More recently, we developed other rodent genetic EE models by combining in utero electroporation with CRISPR gene editing (IUE-CRISPR).
The talk will describe our findings using these models to study three different EIEEs cause by mutations in SCN8A, SPTAN1 and STRADA. Our studies of mouse and patient iPSC models of EIEE13 due to de novo dominant SCN8A mutations show gain-of-function increased persistent or resurgent sodium current leading to neuronal hyperexcitability. We modeled EIEE5 SPTAN1-associated epilepsy with embryonic rat IUE-CRISPR and found that Sptan1 deletion altered cortical pyramidal cell morphology with loss of inhibitory innervation. Similar morphological defects were seen with overexpression of human mutant SPTAN1 and in EIEE5 patient iPSC-derived neurons.
In the last part of the talk, I will discuss our recent studies of PMSE (polyhydramnios, megalencephaly and symptomatic epilepsy) caused by autosomal recessive STRADA mutations, using patient-derived iPSCs grown in 2-D cultures and as cortical organoids. Taken together, our work suggests that combining human iPSC and animal models of EIEEs offers great promise for mechanistic understanding of these severe childhood genetic epilepsies, and should provide useful platforms to identify novel therapies.