CRNL conference of Moran Rubinstein "Therapy Development for DEEs Using Mouse Models"

Abstract

Preclinical models of developmental and epileptic encephalopathies (DEEs) are essential tools for uncovering disease mechanisms, identifying biomarkers, and testing emerging therapies. Our research utilizes mouse models of three key DEEs: CHD2-DEE, GRIN2D-DEE, and SCN1A Dravet syndrome, to translate genetic findings into therapeutic strategies.

We recently characterized a Chd2 frameshift mutation model that exhibits core features of CHD2-DEE, including motor deficits, autistic-like behaviors, and heightened seizure susceptibility. These phenotypes provide clear experimental readouts for evaluating existing and novel pharmacological interventions.

In a model of GRIN2D-DEE, mice carrying the recurrent p.Val667Ile gain-of-function mutation show profound mortality, severe spontaneous brain activity abnormalities, and motor and cognitive impairments. Electrocorticography (ECoG) revealed distinctive oscillatory signatures analogous to patient EEGs, which may serve as translational biomarkers. Pharmacological testing showed an adverse effect of ketamine and modest improvements with memantine and phenytoin.

For Dravet syndrome, we developed a canine adenovirus type 2 (CAV)-mediated gene therapy to deliver a codon-optimized SCN1A transgene post-seizure onset. Targeted injections of CAV-SCN1A into the hippocampus or thalamus improved the survival of Dravet mice, reduced epileptic spikes and spontaneous seizures, protected against thermally induced seizures, and restored impaired cognitive function. These findings offer compelling proof of concept for gene therapy as a treatment for both epileptic and non-epileptic Dravet comorbidities post-seizure onset.

Together, these genetically engineered mouse models faithfully recapitulate hallmark features of human DEEs and provide a robust experimental platform for understanding pathophysiology and accelerating the development of targeted precision therapies.