Louis Dang, M.D., Ph.D.

Recently, there has been a large amount of discovery regarding which gene mutations can cause epilepsy and neurodevelopmental disorders. While this information has resulted in a handful of specific therapies, there remains a large number of gene mutations that lack a clear mechanistic explanation of a neurodevelopmental defect. Dr. Dang’s laboratory is focused on understanding the pathophysiology of genetic causes of epilepsy and neurodevelopmental disorders by using human stem cell models in order to develop novel, precision therapies.

1. Cerebral organoid model of STRADA-related epilepsy and megalencephaly. Recently, there has been a large amount of discovery regarding which gene mutations can cause epilepsy and neurodevelopmental disorders. While this information has resulted in a handful of specific therapies, there remains a large number of gene mutations that lack a clear mechanistic explanation of the neurodevelopmental defects. With our collaborators, we use human stem cell models, two- and three-dimensional neuronal cultures, multiple-electrode array recordings, and calcium imaging to determine how pathogenic variants in STRADA that result in mechanistic target of rapamycin (mTOR) pathway hyperactivity alter early cortical development and cause epilepsy.
2. Amplifiying Nav1.1 expression by targeting upstream open reading frames (uORFs). One of the most prevalent developmental and epileptic encephalopathies is Dravet Syndrome, caused by heterozygous loss of function variants in the SCN1A gene. This causes a reduction of the voltage-gated sodium channel encoded by SCN1A, Nav1.1. In many genes, including SCN1A, there are translation start codons and open reading frames upstream of the primary start codon that can interfere with the efficiency of translation of the main protein product. We aim to target these uORFs to amplify the expression of the non-pathogenic copy of SCN1A as a therapeutic strategy.
3. Modeling SCN1B-related developmental and epileptic encephalopathy. Biallelic pathogenic variants in the SCN1B gene cause severe developmental and epileptic encephalopathy (DEE) that can have clinical features shared with Dravet Syndrome. In collaboration with Dr. Lori Isom and Dr. Jack Parent, we differentiate patient-derived stem cells into neuronal cultures in order to explore how pathogenic variants in SCN1B cause neuronal dysfunction and epilepsy.