DSF Funded Research 2017-05-10T15:37:10+00:00

DSF HAS CONTRIBUTED

$0

TO RESEARCH PROJECTS

DSF is dedicated to funding the highest caliber research on Dravet syndrome and associated epilepsies. Our focus is on research projects that will find new treatments and improve the quality of life for those living with an ion channel epilepsy. DSF places a high priority on funding research that has a clear path to genetic understanding, clinical application, and/or therapeutic development.

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Awards

Jeffrey Calhoun, PhD – Northwestern University
jeffrey-calhoun-phd

$50,000 Postdoctoral Fellowship (1 year project)

Target validation of thalamic T-type calcium channels in a mouse model of Dravet syndrome

Modifier genes influence the severity of epilepsy in Dravet Syndrome and other genetic epilepsies. These epilepsy modifier genes may represent targets for the design of novel therapeutic interventions. We previously identified a modifier gene, Cacna1g, that influences seizure susceptibility in a mouse model of Dravet Syndrome. One goal of this fellowship is to determine whether Cacna1g and related gene Cacna1h are potential molecular targets for therapy using genetic and pharmacological tools in a mouse model of Dravet Syndrome. The other goal of this fellowship is to map the neuronal circuits activated during seizure initiation and propagation in a mouse model of Dravet Syndrome.

aliesha-griffin-phdAliesha Griffin, PhD – University of California, San Francisco 

$50,000 Postdoctoral Fellowship (1 year project)

Optimization of clemizole as a novel treatment for Dravet syndrome

There is a significant need to develop new therapeutic treatments for Dravet syndrome patients as many children suffer persistent drug resistant seizures. Like Dravet syndrome patients, zebrafish with a mutation in SCN1A gene also have seizure-like behaviors.The antihistamine clemizole was able to significantly reduce these seizure-like episodes. However, antihistamines are typically not recommended for Dravet syndrome patients. By modifying the chemical structure of clemizole we can remove its antihistamine activity and improve its antiepileptic properties. These new compounds will be tested for antiepileptic activity using our Dravet syndrome zebrafish model. I anticipate these new versions of clemizole will provide a platform for developing a new treatment for Dravet syndrome.

evangelos-kiskinis-phdEvangelos Kiskinis, PhD – Northwestern University

$165,000 – Research Grant (2 years)

Using patient specific iPSC-derived neurons to identify molecular biomarkers of drug treatment responsiveness in Dravet syndrome

Dravet syndrome remains particularly difficult to treat, with one third of all patients failing to respond to any of the currently available anti-seizure medication. In all cases it is hard to predict how a patient will respond to a drug and clinicians often have to resolve to a trail-and-error approach that can have devastating repercussions for patients and their families. Using Dravet patient-specific stem cells we aim to carefully examine brain cells from patients that have shown good seizure control after drug treatment as well as patients that have been completely refractory to drug treatment. By studying the electrical patterns, the molecular properties and the responses to drugs of these brain cells grown in a dish we aim to: a) understand what makes brain cells respond well to drugs, and b) determine whether we can predict what drug would work best for each patient simply by studying their cells. If successful, our approach will have a major impact in how we diagnose and treat Dravet as well as patients suffering with other kinds of epilepsies.

dennis-lal-phdDennis Lal, PhD – The Broad Institute 

$150,000 – Research Grant (2 years)

A Novel System to evaluate SCN1A Pathogenicity   

Predicting the consequences of mutations identified in clinical screens is far from easy. This is particularly true for genes like SCN1A where variants can be neutral or lead to a wide spectrum of disorders. We will develop novel methods to computationally distinguish pathogenic from benign variants in SCN1A and related genes in patients with Dravet syndrome (DS) and related epilepsies. In our analyses, we will incorporate chemical, biological and a wide range of additional information of mutations in DS-genes to identify differences between patients and controls. The developed methods and findings will be available online to aid variant prediction and drug development.

ruth-westenbroek-phdRuth Westenbroek, PhD – University of Washington

$164,000 – Research Grant (2 years)

Understanding the mechanisms and efficacy of cannabidiol (CBD).

Dravet Syndrome (DS) is one of the most severe childhood neuropsychiatric diseases, with symptoms including febrile seizures and intractable epilepsy, developmental delay, ataxia, sleep disorder, autistic-like behaviors, frequent premature death, and profound cognitive deficit. Life-threatening pediatric epilepsies such as DS are unresponsive to standard therapies. Clinical and preclinical results suggest that cannabidiol (CBD), a non-psychoactive derivative of marijuana, may have novel antiepileptic effects. We will test the hypothesis that CBD attenuates or completely eliminates thermally evoked seizures, spontaneous seizures and/or sudden unexpected deaths using our mouse model of DS. Mice with heterozygous loss-of-function mutations in the Scn1a gene encoding Nav1.1 voltage-gated sodium channels have been shown to be an exact phenocopy of the human DS disease and provide us a unique opportunity to understand the mechanism of action of CBD. Determination of the underlying mechanisms will not only provide a solid basis for the development of a new class of anti-epileptic medicines to benefit pediatric epilepsies but also help the field to better understand key physiological processes that can be targeted to control intractable seizures. The mechanisms investigated here will help guide the next stages of this research in our attempt to discover potentially effective drug combinations for intractable epilepsies.

orrindevinsky_0572Orrin Devinsky, MD – NYU Comprehensive Epilepsy Center and the Saint Barnabas Institute of Neurology and Neurosurgery. 

$50,000 – Ataluren Trial

PTC Therapeutics, the Dravet Syndrome Foundation, and FACES are sponsoring a trial of Ataluren to treat children with treatment-resistant epilepsy associated with Dravet Syndrome or CDKL5 due to stop codon (nonsense) mutations. These are DNA changes in which one DNA nucleotide is substituted for another one and instead of the three letter DNA sequence coding for an amino acid, it codes for a message to prematurely stop the amino acid chain and prematurely terminate the SCN1A or CDKL5 protein, resulting in a roughly 50% reduction in the amount of functional protein since these partial proteins are typically metabolized rapidly by nerve cells. Eight children with Dravet Syndrome and eight children with CDKL5 will be enrolled in this double-blind placebo controlled crossover study.

stephanie-makinson-phdStephanie Makinson, PhD – The Gladstone Institutes

DSF & AES Early Career Research Partnership – $45,000 (1 year project)

The therapeutic potential of the thalamus in Dravet syndrome

Dravet syndrome (DS) is a severe childhood epilepsy for which there is no cure and current treatments often cause major side effects. Most patients with DS have a mutation in the gene, SCN1A, which changes the function of the SCN1A protein and causes seizures. While inhibitory cells in the thalamus express high levels of SCN1A, we only recently learned that this region of the brain is abnormal in Dravet syndrome. With a well-established mouse model of DS that expresses the mutated human Scn1a gene, we showed, for the first time, that the thalamus is pathological and can generate epileptic activity in Dravet syndrome mice. We then manipulated the activity of the inhibitory cells in the thalamus by delivering light specifically to these cells, which interrupted ongoing seizures in freely behaving DS mice. In the proposed project, our goal is to use novel optical approaches to either disrupt or order the activity of inhibitory cells in the thalamus to determine if they cause seizures in Dravet syndrome mice. This work will serve as a proof-of-concept that we could target the thalamus to treat, and potentially cure, Dravet syndrome.

Alex Nord, PhD – University of California, Davis

DSF Research Award – $110,000 (2 year project)

Regulation of SCN1A expression as pathogenic mechanism in Dravet Syndrome

The majority of individuals with Dravet Syndrome (DS) carry mutations in the SCN1Agene, causing a non-functional Nav1.1 protein to be produced in the brain. However, other genetic factors beyond SCN1A coding mutations likely account for the substantial remaining DS causal burden. The activity of genes, such as SCN1A, is controlled by regulatory DNA elements that turn genes on at the right time and place during development. We hypothesize that mutations in regulatory DNA elements that controlSCN1A activity in the brain represent a significant genetic mechanism in DS and SCN1A-associated disorders. The goals of this study are to understand the role of regulatory DNA elements and SCN1A gene expression using mouse models and genomic technologies. These experiments may reveal novel pathological mechanisms and improve genetic diagnosis in DS by enabling screening of important regulatory DNA not captured by current tests.

John C. Oakley, MD, PhD – University of Washington

DSF Research Award – $160,000 (2 year award)

Understanding the relationship between gene mutation, seizures, and cognitive impairment in Dravet syndrome

Seizures and co-morbidities in Dravet syndrome (DS) are not well treated with current therapies and no cure exists. In most cases, DS is caused by mutations in the gene SCN1A resulting in reduced expression of a voltage-gated sodium channel Nav1.1 critical to the excitability of neurons. Work by myself and many others shows that inhibitory cells in the nervous system are particularly effected. We hypothesize that the resulting changes in network function are the cause of seizures and co-morbidities such as cognitive disability. As seizure frequency and severity increases prior to difficulties with memory, learning, and other cognitive functions, it is tempting to attribute impairments to seizure-related brain injury which, if involving cell death, may be irreversible. This has led to a focus on improved seizure control as the primary treatment for cognitive disability. However, recent cognitive outcome studies failed to demonstrate a relationship between seizure type and severity and outcomes. In addition, in our own work in mouse models of DS, we have not found evidence of cell death. This suggests that the network remains, in principle, intact and that restoring normal SCN1A function, even after seizures have begun, may substantially improve network function, seizure control, and cognition. In the proposed study, we seek to determine in our well-validated mouse model of DS whether a reduction in Scn1a expression beginning in adulthood, in the absence of prior seizures, is sufficient for seizure susceptibility and cognitive impairment. To determine whether, under optimal conditions, restoring Scn1a expression, gene therapy, improves cognition and seizures. These studies will provide insights into the potential outcome of gene therapy under the best conditions in which near total correction of the genetic defect is expected and provide preliminary data to support further, more detailed work into the specific brain regions, cell-types, and degree of restored Scn1a expression required to adequately treat seizures and multiple comorbidities, information critical to the development of potential gene therapy in humans.

Samir Das, PhD – University of British Columbia

DSF Postdoctoral Fellowship – $50,000 (1 year project)

Structure and function of the sodium channel Beta 1 subunit: a target for Dravet syndrome mutations

Our neurons can mediate extremely rapid messages through the use of electrical signals. Such signals arise from the movement of tiny charged particles such as sodium ions into the cell. The sodium ions can only enter the cells through a protein, termed ‘sodium channels’. Their opening and closing decide how much sodium can enter the cell which directly affects the brain function. Simple changes in the genetic code can create faulty channels leading to severe epilepsy and Dravet syndrome to infants. Here, we will solve the high resolution structures of the sodium channel both “normal” and “diseased” condition which will shed light on the disease mechanism.

Alison Muir, PhD – University of Washington

DSF Postdoctoral Fellowship – $50,000 (1 year project)

Dravet Syndrome – Where are the missing mutations?

Making a genetic diagnosis in Dravet syndrome is important for many reasons. First, it gives families and physicians insight into disease management and risks for further complications. It also helps discussion about recurrence risk for future pregnancies and influences medication decisions. Finally, it allows researchers insight into how the disease manifests and provides avenues for drug development. However, for 20% of families with Dravet syndrome, no genetic cause is identified. Certain types of mutations are missed by conventional testing and may be present in patients without a genetic diagnosis. We propose to use innovative approaches to hunt for two types of these “missing mutations”: 1) “mosaic” mutations of SCN1A found in only a subset of cells and tissues. 2) “regulatory” mutation that cause changes to how much protein is made.

Elaine C. Wirrell, MD – Mayo Clinic

DSF Research Award – $60,000 (1 year project)

Dravet Syndrome North American Consensus Project (Funding provide through an unrestricted grant from GW Pharmaceuticals)

A core group of pediatric epilepsy specialists, with input from Dravet Syndrome Foundation, has identified important clinical issues relating to the diagnosis and management of patients with Dravet syndrome, focusing specifically on diagnostic testing, course of epilepsy, treatment of seizures (both prophylactic treatment as well as management of status epilepticus), developmental concerns and associated co-morbidities (i.e., sleep disorders, gait problems, autonomic concerns, etc). A panel consisting of 18-20 experts on Dravet syndrome, (consisting of both families of children with Dravet syndrome as well as US and Canadian neurologists with particular expertise in managing patients with this type of epilepsy) will be convened. The goal of this study is to utilize a modified Delphi consensus method to establish best practice guidelines for:
a. Timely diagnosis of Dravet syndrome in a cost effective manner
b. Pharmacologic and dietary treatment of Dravet syndrome to maximize seizure control, reduce frequency of status epilepticus and improve long- term developmental outcomes
c. Identification and management of co-morbidities associated with Dravet syndrome

Theodore R. Cummins, PhD – Indiana University

DSF Research Award – $150,000 (2 year project)

Targeting resurgent sodium currents for treatment of Dravet syndrome

Dravet syndrome (DS) can be devastating and new treatment strategies are needed. In many individuals with DS, genetic abnormalities reduce the activity of the Nav1.1 sodium channel. This reduces inhibitory tone, leading to overactive brain networks and seizures. Reducing the activity of Nav1.6 sodium channels could restore the balance between excitation and inhibition, effectively normalizing network activity. This project will study Nav1.1 and Nav 1.6 channels identified in patients with different types of epilepsy. The action of several promising compounds, including cannabidiol, on these human brain sodium channels and on brain slices from a mouse DS model will be examined. These experiments should help develop a novel treatment strategy and potential drug candidates for Dravet syndrome.

Dr. Cummins’ One Year Update
Published Paper

Alfred L. George, Jr., MD – Northwestern University

DSF Research Award – $150,000 (2 year project)

Novel Pharmacological Therapy for Dravet Syndrome

Dr. George and his collaborators Dr. Jennifer Kearney and Dr. Christopher Thompson will investigate the mechanisms underlying a serendipitous observation that GS967, a novel compound with unique effects on sodium channels, prevents premature death in a mouse model of Dravet syndrome. Specifically, they will determine if GS967 prevents seizures and, if it does, then they will examine how it affects electrical activity in the brain. Because GS967 has many properties associated with a successful drug, the investigators hope that their studies will guide further development of this and related chemical compounds as potential treatments for Dravet syndrome and other childhood epilepsies for which there are no cures.

Dr. George’s 2015 AES poster presentation

MacKenzie Howard, PhD – University of California, San Francisco

DSF Postdoctoral Fellowship – $50,000 (1 year project)

Neural progenitor cell transplantation for the study and treatment of Dravet syndrome

Dr. Howard’s first research goal is to test the effectiveness of cell transplantation therapy for treating Dravet syndrome in a mouse model. This technique involves transplanting non-DS cells into a brain region called the hippocampus, where they develop into specialized inhibitory neurons. Such transplantation has been shown to reduce both seizures and comorbidities in other mouse models of epilepsy. His second goal is to use this technique to transplant DS neurons into the hippocampus of non-DS mice. This will allow him to study how the DS neurons develop, connect, and communicate with other cells in a seizure-free environment and give insight into how various functions of individual neurons are altered.

Jacy Wagnon, PhD – University of Michigan

DSF Postdoctoral Fellowship – $50,000 (1 year project)

Brain transcriptomes in SCN1A and SCN8A related epileptic encephalopathies

The majority of Dravet syndrome cases are caused by mutations in the sodium channel gene SCN1A. Mutations in the related gene SCN8A have recently been discovered in patients with related disorders. Mutations in SCN1A and SCN8A cause severe, early-onset, drug-resistant seizures with a high risk for SUDEP (sudden unexpected death in epilepsy). Mouse models carrying patient mutations in SCN1A and SCN8A exhibit seizures and premature death. Dr. Wagnon will analyze gene expression in these two mouse models to identify common, shared pathological pathways that will provide new targets for treatment and prevention of seizures and SUDEP.

Published Paper

Michael Hammer, PhD – University of Arizona

DSF Research Award – $184,000 (2 year project)

Identifying modifier genes in patients with SCN1a haploinsufficiency using whole exome sequencing

Two questions commonly asked by parents after their child has been diagnosed with Dravet syndrome (DS) are (1) Is this genetic and am I responsible?, and (2) What does my child’s mutation type mean for future outcome? This project will attempt to help us better answer the second question. Most cases of DS are caused by mutations in the SCN1A gene. These mutations negatively affect how sodium ion channels work and result in epilepsies of varying severity. However, more than half of the cases of classical DS result from a single class of mutation (called a truncation) that causes one of the two copies of the gene that we usually inherit from our parents to be lost. This research project will explore the role that other genes, sometimes known as “modifiers”, may play in causing clinical variation among patients with truncation mutations at SCN1A.

Se Hee Kim, MD and Linda Laux, MD – Lurie Children’s Hospital

DSF Research Award – $50,000 (1 year project)

Predictive Factors for Long-Term Cognitive Outcome in Dravet Syndrome

Correct diagnosis and subsequent adjustments of antiepileptic drugs improve seizure control and cognitive performance in patients with Dravet syndrome. However, association between early diagnosis or early appropriate medical therapy and improved long term development remains presumptive. Dr. Laux and Dr. Kim propose to identify predictive factors for favorable cognitive outcome, in cohort of 135 Dravet syndrome patients followed from 2008 to 2013 at the Ann & Robert H. Lurie Children’s Hospital Northwestern University. They believe that early detection and early appropriate management will lead to a better long-term cognitive outcome in Dravet syndrome patients.

2014 American Epilepsy Society Meeting Poster

Yvonne Wu, MD, MPH – University of California, San Francisco

DSF Research Award – $163,000 (18 month project)

Incidence and Predictors of DS: A Population Based Study

The frequency of Dravet syndrome in the general population is unknown. Making an early diagnosis is crucial to providing optimal treatment and improving long-term outcome. Although early predictors of Dravet syndrome have been described, these have yet to be validated in a general U.S. population. We hypothesize that Dravet syndrome is more common than previously recognized, and that reliable predictors during the first year of life indicate which infants with seizures will likely go on to develop Dravet syndrome. In a large birth cohort of over 120,000 infants born in Kaiser Permanente Medical Care Program in Northern California, we will review all inpatient and outpatient medical records to determine the incidence of Dravet syndrome based on established clinical criteria, and determine how many of these individuals have undergone genetic testing. We will then determine the seizure characteristics that increase the risk of Dravet syndrome. Our overall goal is to raise awareness of this often devastating disorder by determining the incidence of Dravet syndrome in the general population, and to find new ways to improve early diagnosis, and thus improve quality of care.

Published Abstract

Jokūbas Žiburkus, PhD – University of Houston

DSF Research Grant – $184,000 (2 year project)

Adenosine A1 Agonist Control of Seizure Activity in Dravet Syndrome

Jokūbas Žiburkus’ laboratory at the University of Houston found that a neurotransmitter-like molecure – adenosine A1 receptor agonist, can effectively control fever-induced or febrile seizures, in a genetically engineered mouse model of Dravet syndrome. Žiburkus will test the hypothesis that the adenosine treatment during early development can prevent the later formation of chronic epilepsy and stabilize brain activity long-term. These studies will be accomplished in collaboration with Dr. Jeffrey Noebels from Baylor College of Medicine, using advanced electrophysiological and fast functional imaging techniques. In summary, Žiburkus stated: We are highly honored and excited by DSF’s sponsorship of this timely and important project. At this pre-clinical experimental stage we must be cautious about interpreting our results, yet hopeful about a potential that pharmacological modulation of the adenosine A1 receptor represents a novel and clincally relevant therapeutic target for Dravet syndrome and other forms of pediatric epilepsies.

Annapurna Poduri, MD, MPH – Boston Children’s Hospital

DSF Research Award – $110,000 (Year Two funding)

Genetics of Severe Early Onset Epilepsies

Epilepsy affects approximately one percent of the population and one in 200 children. A subset of children with epilepsy present in the first year of life with an early onset epileptic encephalopathy syndrome consisting of severe, medically intractable epilepsy and ultimately intellectual disability. While it is well established that genetic factors contribute substantially to the causes of epilepsy, there are still few known genetic etiologies for many of the early onset epileptic encephalopathies. These syndromes include severe myoclonic epilepsy of infancy (Dravet syndrome), infantile spasms, early infantile epileptic encephalopathy with suppression bursts (Ohtahara syndrome), malignant migrating partial epilepsy of infancy, and early myoclonic epileptic encephalopathy. Though they are distinct clinical syndromes, the few genes identified to date with any of them have been associated with a range of phenotypes, such that the discovery of a new gene for any one syndrome would represent an important addition to the currently very limited list of potential genetic etiologies for this group of serious epilepsy conditions. These discoveries will deepen our understanding of the developmental pathways important in epilepsy and will point us toward novel approaches to rational pharmacological treatment for epilepsy.

Jingqiong “Katty” Kang, MD, PhD – Vanderbilt University

DSF/CURE Research Award – $150,000 (1 year project)

Probing synaptic changes in a novel mouse model of severe epilepsy with nanoparticle-enabled 3D super-resolution imaging

Dr. Kang’s work focuses on understanding the role of GABAA receptors (GABR) in the etiology of epilepsies, including Dravet Syndrome. Normal brain function requires precise balance between excitation and inhibition. Too much excitation or too little inhibition will result in seizures or epilepsy. GABR are a family of genes encoding a total of 19 protein subunits which, in different combinations, mediate the majority of brain inhibition. A single coding change, like point mutation, in the any of the genes of this protein family can cause different kinds of epilepsy. Some of these epilepsies are mild and remit as children grow up but some are severe and may present with many other neurodevelopmental defects for unknown reasons. Dr. Kang’s team will try to understand the mechanisms underlying the pathophysiology of epilepsy as caused by mutations in GABR, as well the phenotypic variations, and to develop mechanism-based therapeutic strategies.

Published Paper

Annapurna Poduri, MD, MPH – Boston Children’s Hospital

DSF Research Award – $110,000 (1 year project)

Genetics of Severe Early Onset Epilepsies

Epilepsy affects approximately one percent of the population and one in 200 children. A subset of children with epilepsy present in the first year of life with an early onset epileptic encephalopathy syndrome consisting of severe, medically intractable epilepsy and ultimately intellectual disability. While it is well established that genetic factors contribute substantially to the causes of epilepsy, there are still few known genetic etiologies for many of the early onset epileptic encephalopathies. These syndromes include severe myoclonic epilepsy of infancy (Dravet syndrome), infantile spasms, early infantile epileptic encephalopathy with suppression bursts (Ohtahara syndrome), malignant migrating partial epilepsy of infancy, and early myoclonic epileptic encephalopathy. Though they are distinct clinical syndromes, the few genes identified to date with any of them have been associated with a range of phenotypes, such that the discovery of a new gene for any one syndrome would represent an important addition to the currently very limited list of potential genetic etiologies for this group of serious epilepsy conditions. These discoveries will deepen our understanding of the developmental pathways important in epilepsy and will point us toward novel approaches to rational pharmacological treatment for epilepsy.

Jack M. Parent, MD –  University of Michigan

DSF Research Award – $250,000 (2 year project)

Readthrough Treatment of Dravet Syndrome Caused by Nonsense SCN1A Mutations

Dr. Parent and collaborators Dr. Lori Isom and Dr. Miriam Meisler will investigate whether readthrough therapy is a clinically viable treatment for Dravet syndrome patients who carry stop codon nonsense mutations. With a new technique, the induced pluripotent stem cell (iPSC) method, they have a unique opportunity to study the effects of mutations in neural cells by deriving neurons from patients’ own skin cells. In addition, they will collaborate with Dr. Richard Gatti, a Professor of Human Genetics at UCLA, who is developing new and improved readthrough compounds. Parent and his colleagues will test whether gentamicin, PTC124, or newer compounds will increase normal sodium channel levels and restore channel function in patient-derived neurons. They will also examine whether mice with a Dravet syndrome knock-in premature termination (stop) codon nonsense mutation (a point mutation in a sequence of DNA) will respond to readthrough therapy with a decrease in seizures and normalization of sodium channel function.

Scott Baraban, PhD – University of California, San Francisco

DSF Research Award – $100,000 (1 year project)

Drug Discovery in a Zebrafish Model of Dravet Syndrome

Dr. Baraban and his team are using Dravet syndrome zebrafish mutants to screen and identify novel pharmacological treatments for Dravet syndrome patients. Zebrafish are commonly used in research due to their genetic and experimental accessibility. This project was the starting point for Dr. Baraban’s newest research project (see below) recently co-funded by the DSF and CURE. After publishing a paper from this study (below), Dr. Baraban and his lab released their database of compounds screened in zebrafish, found via the “Database” button below. Note that this database contains both published compounds and unpublished compounds and will be periodically updated by the Baraban Lab.

Published Paper
Drug Discovery Database

Scott Baraban, PhD – University of California, San Francisco

CURE & DSF Research Award – $250,000 (2 year project)

Gene Profiling and High-Throughput Drug Screening in a Zebrafish Model of Dravet Syndrome

Pediatric epilepsies are associated with developmental or cognitive co-morbidities and are not well controlled by available drugs. Unfortunately, existing drug discovery programs are not designed to address this problem, as they are primarily based on acute or acquired seizures in adult rodent models of the epilepsies. Dr. Baraban seeks to shift current research in the epilepsy field in two ways. First, by utilizing immature zebrafish models designed to mimic known single-gene mutations seen in children (for example, Dravet syndrome), he will establish a drug discovery program targeted at pediatric epilepsy that also incorporates large-scale microarray gene analysis. Second, by focusing on the zebrafish model, he will establish a new template for high-throughput cost-effective drug screening with distinct advantages over current rodent-based approaches.

View Update

Opko Health, Inc.

DSF Research Award – $50,000 (1st year of project grant)

OPKO Research Project

More than 75% of children who have been diagnosed with Dravet syndrome have a defective SCN1A gene. As a result, the defective gene is not producing enough functional protein, leading to a diseased state. OPKO Health, Inc., a South Florida based pharmaceutical company, has developed new technology to increase SCN1A protein production. Early tests have shown a promising increase in this protein level in a Dravet patient’s fibroblast and in human cell lines, such as a neuroblastoma. This research is applicable to all mutation types. OPKO is committed to further the development of this work and to seek health authorities’ approvals worldwide.

Sooky Koh, MD, PhD – Children’s Memorial Hospital

DSF Research Award – $100,000 (1 year project)

Novel Therapies to Block Epileptogenesis in Dravet Syndrome Mice

Using a mouse model of Dravet syndrome, Dr. Koh and her colleagues will investigate three novel strategies to treat Dravet syndrome and understand epileptogenesis, the process by which the developing brain evolves to produce repeated seizures. They will utilize anti-inflammatory therapy; use dietary interventions; and, finally, investigate the use of an enriched environment on the impact and outcome of seizures. The promise of this research program is in identifying treatments that minimize the detrimental effects of recurrent seizures, modify disease progression, and prevent chronic epilepsy.

Sebastian Maier, MD, PhD and Massimo Mantegazza, PhD

CURE & DSF Research Award – $150,000 (1 year project)

Cardiac arrhythmias and SUDEP in SMEI and other Nav1.1 (SCN1A) related epilepsies

Dravet syndrome is a severe and drug resistant form of epilepsy, characterized by high mortality rates. Sudden unexpected death in epilepsy (SUDEP) is the most frequent cause of death for individuals with Dravet syndrome. The majority of individuals with Dravet syndrome carry mutations in a sodium channel subtype that is found in the brain, heart and nerves. Drs. Maier and Mantegazza will study the role of this sodium channel subtype in the heart of a mouse model of Dravet syndrome in order to investigate the occurrence and mechanism of arrhythmias and their possible involvement in SUDEP.

Final Report

Jack M. Parent, MD & Ian Miller, MD

ICE & DSF Research Award (co-funded for life of project)

International Dravet Syndrome/Ion Channel Patient Registry (IICEPR)

This patient registry, owned by the University of Michigan and Miami Children’s Hospital, collects basic information and genetic test results of individuals with Dravet syndrome and related epilepsies worldwide and is available to all interested researchers at no cost. The establishment of this registry will expedite future clinical trials and will serve to improve communication of ideas amongst interested researchers, as well as assure rapid distribution of any new information that may benefit patients and their families.