Last night at their annual Research Roundtable Meeting, the Dravet Syndrome Foundation (DSF) announced funding for five new research grants. DSF is pleased to be funding grants that focus on important topics for individuals with Dravet syndrome, including investigation of metabolic dysfunction, exploration of novel therapeutic targets for disease-modifying therapies, and exploration of changes to the way the brain communicates in Dravet syndrome. Funding for these five grants totals $650,000, bringing DSF’s total research funding since 2009 to over $5.6M.
This year, another organization, JAM for Dravet, has stepped forward to co-fund two of these projects with DSF. JAM (Julian’s Awareness Movement) for Dravet was inspired by Julian Chang, who was diagnosed with Dravet syndrome at one year old. His parents, Daniel and Deb, established the foundation to help accelerate cutting-edge pathways to a cure, raise awareness, and foster a robust community of support for families affected by Dravet syndrome. DSF appreciates their important contribution to advancing research efforts for Dravet syndrome.
Read on to learn more about the 2021 awardees and read descriptions of their proposed projects.
Research Grants – $150,000 two-year awards
- Lymphoblast cell lines as a model to uncover metabolic defects in Dravet Syndrome: Manisha N. Patel, PhD, University of Colorado, and Kelly G. Knupp, MD, Children’s Hospital Colorado.
Dr. Manisha Patel is a Professor in the Department of Pharmaceutical Sciences at the University of Colorado Anschutz Medical Campus. She received her Ph.D. in Pharmacology and Toxicology at Purdue University, and postdoctoral training in Neuroscience at Duke University. The primary theme of her laboratory\’s research is to understand the redox and metabolic basis of epilepsy and develop metabolism-based therapies for its treatment. Her research efforts have provided compelling evidence for the role of metabolic dysfunction in acquired epilepsy and more recently in a zebrafish model of Dravet syndrome.
Dr. Kelly Knupp is an Associate Professor of Pediatrics and Neurology at the University of Colorado. She received her medical degree from the University of New Mexico – School of Medicine, completed her residency in Pediatrics at Children’s Hospital of New York followed by Pediatric Neurology Residency at Columbia University at Children’s Hospital of New York. After her residency, she trained as a Clinical Fellow in Pediatric Epilepsy at the Columbia Comprehensive Epilepsy Center at New York Presbyterian Hospital. Dr. Knupp now practices at Children’s Hospital Colorado in Aurora, CO. and is the Associate Research Director of Neuroscience Institute and Director of the Dravet Program. Her interests are epileptic encephalopathies including Dravet syndrome and infantile spasms. She was a founding member of the Pediatric Epilepsy Research Consortium and continues on the steering committee. This group focuses on developing collaborative research across the country for children with epileptic encephalopathies. She also serves on the medical advisory boards of the Epilepsy Foundation of Colorado, Roundup River Ranch, and DSF.
Project Description: Dravet syndrome (DS) is a catastrophic developmental and epileptic encephalopathy characterized by intractable early-life seizures, and debilitating comorbidities such as cognitive deficits, developmental delay, sleep disturbances, progressive movement abnormalities and increased risk of sudden unexpected death in epilepsy. Our recent work in a zebrafish model of DS suggests that energy usage at the cell level may be disturbed in DS which forms the basis of this project. It is hypothesized that DS patients will display energy defects which will be reflected in their immortalized blood cells to derive metabolic information. The goal of this proposal is to determine if immortalized blood cells (lymphoblast cell lines or LCLs) from DS patients show energy changes compared to age- and gender-matched controls (including unaffected siblings). We will create LCLs from DS patients and control individuals. We propose to test these LCLs for alterations in energy metabolism using assays which are ongoing in our laboratory. Dr. Kelly Knupp has over 110 DS patients in her clinical care and Dr. Manisha Patel’s laboratory routinely conducts metabolism-based assays in specimens from epilepsy models (mice, rats and zebrafish). This research can demonstrate if and how energy metabolism is altered in DS patients and provide a resource of patient-specific LCLs which can be tested for identification of new drugs, diets and treatment responses for DS and its comorbidities.
- Ketogenic Diet Modulated Brain Energy Metabolism in Dravet Syndrome: 2H MR in a Mouse Model: K. Liu Lin Thio, MD, PhD, and Joel R. Garbow, PhD, Washington University in St. Louis. This grant was co-funded with JAM for Dravet.
Dr. Liu Lin Thio is a Professor of Neurology, Pediatrics and Neuroscience in the Department of Neurology and the Division of Pediatric and Developmental Neurology at Washington University in St. Louis. Dr. Thio is also the Director of the Pediatric Epilepsy Center, the Program Director for the Pediatric Epilepsy Fellowship, and the Director of the Dietary Therapies Clinic for Neurological Disorders. His preclinical research has focused on the antiseizure and neuroprotective mechanisms of the ketogenic diet.
Dr. Joel R. Garbow is a Professor of Radiology within the Biomedical Magnetic Resonance Laboratory (BMRL), Mallinckrodt Institute of Radiology, at Washington University in St. Louis with more than 40 years of experience in magnetic resonance (MR) imaging and spectroscopy. He serves as co-director of the MR component of the Alvin J. Siteman Cancer Center’s Small Animal Imaging Shared Resource and head of the Washington University Intellectual and Development Disabilities Research Center’s Small Animal Imaging Unit. In addition to studies of intellectual and developmental disabilities, his research interests include the use of innovative MRS and MRI methods to quantify placental function and competence and the development and application of novel MR methodologies, including metabolic imaging, for the study of cancer and radiation-induced brain injury in pre-clinical, small-animal models.
Project Description: Children with Dravet syndrome have drug-resistant epilepsy characterized by different seizure types along with developmental regression and intellectual impairment. Dravet syndrome is genetic with the typical cause being a mutation in a subunit of the neuronal, voltage-gated sodium channel. Ion channels mediate the electrical communication between neurons in the brain, and mutations in ion channels are obvious candidates for causing epilepsy, which is characterized by abnormal electrical activity in the brain. However, several clinical observations including the success of the ketogenic diet (KD) in treating various forms of epilepsy suggest that abnormal metabolism also contributes to the disease process. Although an ion channel mutation causes Dravet syndrome, the often good response to the KD seen in patients and results from animal models of Dravet syndrome indicate that disordered metabolism has a role in this epilepsy syndrome. We hypothesize that Dravet syndrome affects two major metabolic pathways involved in energy production – glycolysis and the tricarboxylic acid (TCA) cycle – and that the KD alters the function of these pathways in Dravet syndrome. We will assess these metabolic pathways in commonly used, genetic mouse model of Dravet syndrome with a magnetic resonance imaging (MRI) based technique. We will use this non-invasive method to compare glycolysis and TCA cycle flux in control and Dravet mice when fed a regular diet and when fed a KD diet. The findings will be directly applicable to patients with Dravet syndrome since the same MRI based technique can be used clinically.
- Targeting Molecular Responses to Seizures in Dravet Syndrome: Jacy Wagnon, PhD, Ohio State College of Medicine.
Dr. Jacy Wagnon, is an Assistant Professor in the Department of Neuroscience at Ohio State University. Her laboratory focuses on genetic and molecular mechanisms of developmental and epileptic encephalopathies. She has been investigating pathogenic mechanisms underlying sodium channelopathies, including Dravet syndrome and SCN8A encephalopathy, for more than 8 years. Dr. Wagnon currently serves as a member of the Scientific Program Committee of the American Epilepsy Society, as a contributing editor in Basic Sciences for Epilepsy Currents, as a member of the Epilepsy Gene Curation Expert Panel and the Sodium Channel Variant Curation Expert Panel for ClinGen, and as a review editor for Frontiers in Pharmacology: Ion Channels and Channelopathies.
Project Description: Many individuals with Dravet syndrome (DS) do not achieve adequate seizure control using available drug treatments. These drugs also do not sufficiently treat other symptoms of DS, including behavioral and cognitive impairments. We analyzed gene expression in a mouse model of DS to identify molecular pathways that may not be functioning correctly in DS. We identified very low expression of a gene, Npas4, that functions to counteract the hyperexcitability in the brain that leads to seizures in DS. We predict that if we restore high expression of this gene in DS mice, hyperexcitability in the brain will be reduced, resulting in fewer seizures and improved behavior and cognition. We propose to test this prediction by delivering the Npas4 gene into the brain of DS mice using a virus. This technique is similar to virus-mediated gene therapy that is currently being used to treat spinal muscular atrophy in children. If this treatment is successful in DS mice, it will indicate that the Npas4 pathway is a good target for development of new treatments for Dravet syndrome.
Clinical Research Grant- $150,000 two-year award
- Use of TMS to understand in-vivo the functional pathophysiology of DS and predict treatment response: Simona Balestrini, MD, PhD, and Sanjay Sisodiya, PhD, FRCP, UCL Queen Square Institute of Neurology, London.
Dr. Simona Balestrini is Associate Professor of Child Neurology and Psychiatry at the Neuroscience Department, Children\’s Hospital A. Meyer, and University of Florence. She is also Consultant Neurologist at the Chalfont Centre for Epilepsy and National Hospital for Neurology and Neurosurgery, UCLH, and Senior Clinical Research Fellow at UCL Queen Square Institute of Neurology. Her current research focuses on genomic and neurophysiological tools to understand the causes, course and treatment response of epilepsy.
Dr. Sanjay Sisodiya is an adult neurologist focussing on understanding complex epilepsies, especially those due to genetic alterations, and on translating science to clinical practice for the benefit of people with these serious conditions. He founded and leads a number of international initiatives, including EpiPGX and ENIGMA-Epilepsy. He is also deeply concerned about the effects of climate change on people with epilepsy, for which reason he started a group called EpilepsyClimateChange.
Projection Description: Dravet syndrome (DS) is caused by a genetic change that leads to severe epilepsy with difficult-to-treat seizures, cognitive impairment, other neurological and physical symptoms, and heightened risk of premature mortality. Despite treatment with multiple antiepileptic drugs, people with DS often do not respond to them and there is no treatment to cure DS. Transcranial magnetic stimulation (TMS) is a non-invasive tool ideal for characterising brain activity in people with epilepsy, as it can probe directly the workings of brain circuits in life. We have already applied TMS in people with DS and found very specific changes when compared with people with other epilepsies and healthy controls. These changes suggest that the underlying genetic change causes alteration of neuronal excitability, leading to seizures and other neurological dysfunction. Our findings were in keeping with the changes in brain activity found in animal models of DS. Our work suggests that TMS can be used as a reliable tool to study disease mechanisms in the living brain in people. Our key questions are: what are the mechanisms leading from the genetic change to seizures, cognitive difficulties and other symptoms common in DS? What happens over time to neurons and their connections in the brain in people with DS? How can we use this information to better treat seizures and the other issues in DS? We will use TMS to understand better the alterations of brain activity in a given person with DS, providing the key link between the genetic change and epilepsy, responses to treatments and other outcomes in DS. We will analyse various measures of brain activity over time and in association with treatment and severity of the disease. TMS is a novel, non-invasive, and safe technique in epilepsy, able to tell us what genetic changes cause in the living brain.
Postdoctoral Fellowship – $50,000 one-year award
- Optimizing the Regional Administration of SCN8a-targeting RNAi Therapy: Wenxi Yu, PhD, University of Michigan. This grant was co-funded with JAM for Dravet.
Dr. Wenxi Yu’s interest lies in elucidating pathogenic mechanisms of genetic diseases and translational research leading to novel therapies. He received his Ph.D. degree in Biological Sciences at Wayne State University. His graduate work focused on pathogenic and therapeutic mechanisms of bipolar disorder and Barth syndrome. In 2019, Dr. Yu joined the Meisler laboratory to study developmental epileptic encephalopathy (DEE) and develop therapies for this disorder. Recent studies include effects of somatic mutation of SCN8A on seizures and identification of GABRA2 as a modifier of SCN8A encephalopathy.
Project Description: Mutations in the sodium channel genes SCN1A and SCN8A are a significant cause of Developmental Epileptic Encephalopathies (DEEs), severe seizure disorders. We demonstrated that reduced expression of Scn8a using a specific ASO can prevent the onset of seizures in mouse models of Dravet syndrome and Scn8a encephalopathy. We will build on that success by evaluation of another method for reducing Scn8a expression, the viral administration of an shRNA by injection into targeted brain regions. This method provides two important improvements: longer in vivo persistence that avoids repeated treatments, and protection of spinal motor neurons, that depend on Scn8a. We will use an AAV10 construct with demonstrated effectiveness in reducing Scn8a expression to determine whether regional reduction of Scn8a-N1768D can prevent seizure progression and co-morbidities in these mice.