The Poduri Laboratory and Epilepsy Genetics Program comprise a translational research program with a focus on genetic epilepsies from both a human genetics and a functional modeling perspective.

Our early efforts in gene discovery focused on somatic mosaic, post-zygotic mutations in focal epilepsy related to developmental brain malformations. In addition, we evaluated families with inherited epilepsies. Through our own lab’s studies as well as work with the Epilepsy Phenome/Genome Project and Epi4K, both international NIH-supported epilepsy genetics consortia, we have discovered numerous de novo single-gene causes of severe early onset epilepsies that point not only to dysfunction or disruption of ion channels but also several other processes, including synapse development and early brain organization. We have engaged with parent-led foundations to create registries for patients with pathogenic variants in genes such as PCDH19 and KCNQ2. We continue to apply modern sequencing and analysis methods to the many cases that remain unsolved.

Gene discovery in epilepsy is a first step to understanding the brain developmental processes that are disrupted and lead to epilepsy. Our Lab uses the zebrafish system, an excellent tool for neurodevelopmental studies with a translational ‘readout’ of visible seizures, to study genes important in human epilepsy (e.g., PCDH19). We are developing a screening platform to determine whether novel candidate genes for epilepsy have evidence for pathogenicity and whether they might be candidates in which to screen novel compounds to treat seizures in the future.

We have partnered with the Translational Neuroscience Center, Harvard Stem Cell Institute, and Woolf Lab to conduct studies of neurons derived from patient cell lines representing the genes SCN8A and KCNQ2. Our emerging pilot studies seek to demonstrate the electrophysiological abnormalities that can be detected in this system and to screen abnormal lines with compound libraries in an attempt to discover novel treatments for patients with pathogenic variants in these genes.

Our research program is partnered with our Epilepsy Genetics Clinic, where we see patients with several forms of genetic epilepsies. We have begun conducting gene-specific clinical trials, and we anticipate that these will continue as functional studies in models of genetic epilepsy lead us toward rational and precision treatments for children with severe epilepsy.