The Dravet Syndrome Foundation (DSF) announced the 2020 grant awardees last night at the 11th annual Research Roundtable. DSF is excited to be funding two 2-year research grants and an additional 1-year postdoctoral fellowship. Following this year’s awards, DSF’s total contribution to research projects will be nearly $5 million. The first of the 2-year grants focuses on the development of genetic treatments for Dravet syndrome. While previous approaches have been limited by the large size of the SCN1A gene, the researchers (Drs. Kremer, Rubinstein, and Goldberg) propose a novel approach that uses a larger package, or “vector,” to deliver a healthy copy of the SCN1A gene to specific cells in the brain. The next grant is investigating the mechanisms of sudden unexplained death in epilepsy (SUDEP). The primary investigator, Dr. Metcalf, is interested in how some of the support cells in the brain, called “glia,” respond to seizures and contribute to changes in the brain that may impact the risk for SUDEP. The postdoctoral fellowship this year is for a grant to develop methods that would predict seizures from video recordings. Dr. Somarowthu will leverage machine learning techniques and a mouse model of Dravet syndrome to develop approaches for the prediction and detection of seizures. Below, you can read more about the funded research projects and the lead investigators for each project.
Optimizing a novel SCN1A delivery approach for Dravet syndrome therapy
2-year research grant
Primary Investigators: Eric Kremer, PhD; Moran Rubinstein, PhD; Ethan Goldberg, MD, PhD
Grant Summary: The vast majority of Dravet syndrome cases are caused by mutations in one of the two copies of the SCN1A gene. The SCN1A gene provides instructions to build a protein that forms a sodium channel called “NaV1.1”. Therefore, as Dravet mutations hamper the function of NaV1.1, restoring the activity of this protein with gene therapy is a logical approach to treat the severe epilepsy and Dravet syndrome-associated developmental delay. An obstacle for gene therapy is the large size of the NaV1.1. While most methods of gene transfer cannot circumvent this obstacle, a vector called “CAV-2” can. Our preliminary data, using a beta version of the vector, already demonstrated the therapeutic potential of this approach. Indeed, administration of such gene therapy treatment to Dravet mice, at the onset of severe epilepsy, reduced the occurrence of spontaneous seizures and improved their survival.
We aim to optimize this approach by tweaking the vector to express NaV1.1 in different neuron types, as well as optimizing when and where to inject the vector. Our results will identify the most effective approach for future clinical trials and provide insights into the neuronal basis of the most severe symptoms.
Eric J. Kremer, PhD- Institut de Génétique Moléculaire de Montpellier. EJ Kremer received his PhD from USC, moved to Australia for a post-doc before settling in France. EJK is now the Director Adjoint of Institut de Génétique Moléculaire de Montpellier (France), which is home to 18 research teams. He has directed a virology/immunology/neurobiology lab for ~25 years and has contributed to >120 studies, including those in Nature, Cell, Science, Lancet, NEJM, BMJ, Nat Gen, Nat Neuro, Neuron, JCI, JEM, eLife & PNAS. One of the major themes in his lab is to develop and use vectors for gene transfer to the brain. These vectors are used to identify neural circuitry, and model and treat neurodegenerative diseases, and in particular Dravet Syndrome.
Moran Rubinstein, PhD- Tel Aviv University. Dr. Moran Rubinstein is the Head of the Goldschleger Research Institute and a Faculty member at the Department of Human Molecular Genetics and Biochemistry at the Sackler Faculty of Medicine of Tel Aviv University, Israel. She completed her Ph.D. studies at Tel Aviv University and her postdoctoral training at the University of Washington, Seattle, USA.
For the last decade, Dr. Rubinstein’s research focuses on Dravet syndrome. During her postdoctoral studies, she demonstrated the contribution of different interneurons subtypes to Dravet autistic-like features, hyperactivity, and cognitive impairment . Since establishing her lab in October 2016, her studies demonstrated that the severity of epilepsy in Dravet is correlated with the degree of SCN1A gene loss of function . Furthermore, by analyzing the developmental trajectories of Dravet epilepsy and Dravet-associated comorbidities in mice, Moran’s team demonstrated an uncoupling between convulsive seizures and some of the non-epileptic comorbidities . Finally, using electrophysiological recordings in hippocampal brain slices they showed alterations in the function of excitatory and inhibitory neurons, as well as changes in the processing of synaptic inputs .
“On a personal note, I am honored and delighted that our joint proposal, together with Dr. Eric Kremer and Dr. Ethan Goldberg, ‘Optimizing a novel SCN1A delivery approach for Dravet syndrome therapy’, was funded by the Dravet Syndrome Foundation. By combining our different expertise into one coordinated multidisciplinary effort, we aim to provide an effective gene therapy vector, able to ameliorate the epileptic and non-epileptic phenotypes of Dravet, that can be translated into clinical studies in the future.”
- Rubinstein, M., Han, S., Tai, C., Westenbroek, R.E., Hunker, A., Scheuer, T., and Catterall, W.A. (2015). Dissecting the phenotypes of Dravet syndrome by gene deletion. Brain 138, 2219-2233.
- Nissenkorn, A., Almog, Y., Adler, I., Safrin, M., Brusel, M., Marom, M., Bercovich, S., Yakubovich, D., Tzadok, M., Ben-Zeev, B. and Rubinstein, M. (2019). In vivo, in vitro and in silico correlations of four de novo SCN1A missense mutations. PLoS One 14, e0211901.
- Fadila, S., Quinn, S., Turchetti Maia, A., Yakubovich, D., Ovadia, M., Anderson K., Giladi, M., Rubinstein, M. (2020). Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1aA1783V Drave syndrome mouse model. Epilepsia 61, 2289-2300.
- Almog, Y., Fadila, S., Brusel, M., Mavashov, A., Anderson, K.L., Rubinstein, M. (Accepted) Developmental alterations in firing properties of hippocampal CA1 inhibitory and excitatory neurons in a mouse model of Dravet syndrome. Neurobiology of Disease.
Ethan Goldberg MD/PhD- University of Pennsylvania/CHOP. Dr. Goldberg is Assistant Professor in the Division of Neurology at The Children’s Hospital of Philadelphia and Departments of Neurology & Neuroscience at The University of Pennsylvania, in Philadelphia, PA, U.S.A. Dr. Goldberg is a practicing pediatric neurologist and Director of the Epilepsy Neurogenetics Initiative at The Children’s Hospital of Philadelphia. His lab studies mechanisms of epilepsy in experimental model systems towards the development of novel therapies for neurodevelopmental disorders.
Brainstem glial control of respiration in a mouse model of Dravet syndrome
2-year research grant
Primary Investigator: Cameron S. Metcalf, PhD
Grant Summary: Patients with Dravet syndrome (DS) suffer from seizures as well as numerous behavioral, cognitive, and metabolic comorbidities. Thus, this disorder is a major challenge to not only patients but also parents, caregivers, and providers for those affected. Further, a high mortality rate due to Sudden Unexpected Death in Epilepsy (SUDEP) is a major source of fear and concern for families affected by DS. The purpose of the outlined studies is to explore a novel potential mechanism of SUDEP in DS. While we understand risk factors and mortality in DS, in order to advance this field of study more information is needed to understand the mechanisms contributing to SUDEP. We have instituted a mouse model of DS with important face validity: pharmacoresistance, hyperthermia-induced seizures, spontaneous seizures, and a high mortality rate. Using this model, the studies outlined in this proposal will address changes in respiratory neurocircuitry that affect breathing following seizures. We propose that in DS, changes in the brainstem may be driven by the responses of glial cells to seizures. Further, these studies also include an intervention that may potentially reduce mortality and improve outcomes. Therefore, this project will advance understanding of the mechanisms of SUDEP in DS and provide a potential therapeutic avenue to minimize mortality risk
Cameron S. Metcalf, PhD- University of Utah. Cameron S. Metcalf, PhD, is the Associate Director for the Contract Site for the Epilepsy Therapy Screening Program (ETSP) and a Research Assistant Professor in the Department of Pharmacology and Toxicology in the College of Pharmacy at the University of Utah. Dr. Metcalf is also a Co-Investigator for the Contact Site for the ETSP, under the direction of Karen Wilcox (PI). This work includes the development and validation of animal models and the testing of novel drugs targeted at one or more key therapeutic areas: 1) pharmacoresistant epilepsy, 2) special populations of epilepsy, and 3) disease modification or anti-epileptogenesis. This work has also included the validation of a model of Dravet Syndrome (DS) for potential inclusion as a screening tool in the ETSP. Dr. Metcalf’s dissertation (2008) was centered around cardiovascular risk associated with Status Epilepticus and spontaneous seizures in a rat model of epilepsy. This work identified changes in autonomic regulation of the heart that may contribute to the risk for arrhythmias and Sudden Unexpected Death in Epilepsy (SUDEP). Following this work, Dr. Metcalf transitioned to clinical research and worked on several drug trials covering a wide range of therapeutic targets: migraine, chronic pain, hypertension, and infectious diseases. He then returned to preclinical research, working for a start-up pharmaceutical company focused on neuropeptide-based drug development for epilepsy and pain. This work led to the generation of two galanin-based lead analogs targeted for clinical trials. Dr. Metcalf continues this work today at the University of Utah, where part of his work seeks to identify clinical avenues for galanin-based neuropeptides. Recently, Dr. Metcalf received funding from the ALSAM foundation to study the role of galanin in SUDEP. Dr. Metcalf is dedicated to the continued elucidation of mechanisms that contribute to DS pathology with particular interest in the study of SUDEP and potential therapies that may reduce mortality.
Seizure prediction and detection in a mouse model of Dravet syndrome via machine learning
1-year postdoctoral fellowship
Primary Investigator: Ala Somarowthu, PhD
Grant Summary: Dravet syndrome is a chronic infantile myoclonic epilepsy that is not entirely curable with the available treatments in every patient. Current research is focusing on new technologies for the cure and intermittent relief for a better life without seizures. Impending seizure prediction or early detection can be useful for on-demand intervention for ceasing the seizures. The current study proposed to design a seizure detection/prediction system by implementing advanced machine learning algorithm on extracted behavioral signatures in mouse model of Dravet syndrome. The developed seizure detection system will be further executed in a closed loop framework to facilitate the on-demand intervention.
Ala Somarowthu, PhD- Children’s Hospital of Philadelphia Dr. Somarowthu is a Research Postdoctoral fellow at Children’s Hospital of Philadelphia in the Neurology Department. She received her PhD in Bioengineering with specialization in bio-signal processing from Northeastern University, Boston, MA. Her current work focusses on automatic seizure detection and studying the mechanisms of seizure in the mouse model of Dravet syndrome. Dr. Somarowthu’s long term research interests are to apply signal processing and machine learning tools to solve biological problems. Dr. Somarowthu’s academic training and research experience have enabled her with excellent interdisciplinary background which is essential for the proposed study.