Genetic Determinants of Epilepsy in Murine Systems

PROJECT SUMMARY Developmental and Epileptic Encephalopathies (DEE) are individually rare but collectively substantial neurodevelopmental disorders characterized by debilitating seizures and unremitting neurological comorbidities. Dedicated exome sequencing efforts have led to unprecedented success in DEE gene discovery, with one-third or more cases that are brought to the genetics clinic resulting in a clear genetic diagnosis. This new insight has, in turn, created high expectations for precision or personalized medicine to deliver new therapies to families who otherwise do not have many options for disease mitigation, since conventional drug therapy is ineffective for most symptoms in any given DEE. In principle, gene therapy offers potential for treating any symptom caused by a defective gene because it is based on replacing or eliminating it in situ. Among the barriers to clinical application include the mode and the timing of delivery, particularly for neurodevelopmental disease, and the concern about side effects from unintended impact on gene expression in cell types that do not require attention. The purpose and the design of this renewal proposal is to address these barriers directly using ready manipulable mouse models to examine key issues in the development and progression of DEE and the prospects for gene therapy. First, we will apply new methods explicitly designed to detect epileptiform activity and developmental milestones in mouse pups, representing an understudied but most appropriate age to model a childhood disease. We will then use mouse genetics tools to drive gene expression in different neuron types or developmental ages in these models, in order to determine the cellular etiology and critical window for disease development. Last, we will extend RNA-based gene therapy efforts to these models, testing for both effective mitigation of pathogenic features while monitoring accompanying changes in global gene expression. To accomplish these goals we have assembled a team of four laboratories each contributing complementary expertise. Through this synergistic, collaborative effort, we expect to make significant strides in understanding the basis of disease in three striking models of DEE with the potential to advance new treatments in the clinic.