CURE - Citizens United for Research in Epilepsy It's Time We Found a CURE CURE Epilepsy Research

Grant recipients were selected with the invaluable assistance of the CURE Scientific Advisory Council and the CURE Research Review Board.

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2000-2007 Research Awards

2007 Multidisciplinary Awards

Anderson
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Vatta

Anne Anderson, MD & Matteo Vatta, PhD - Baylor College of Medicine / Houston, TX

Award CENTRAL NEW YORK AWARD, In memory of Christopher Donalty and Kyle Coggins

Myocardial Ion Channel Remodeling: A Candidate Mechanism for Sudden Death in Epilepsy

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of mortality in individuals with epilepsy. This study hypothesizes that cardiac ion channels may be affected by primary genetic or acquired alterations associated with epilepsy, which represent candidate mechanisms in SUDEP. Cardiac ion channel alterations due to either of these mechanisms would predispose the heart to arrhythmia, which is a risk factor for sudden death. The studies will be performed as an interdisciplinary collaboration between Dr. Anderson, an epilepsy researcher, and Dr. Vatta, a cardiovascular researcher with expertise in myocardial remodeling and channelopathies. The interdisciplinary approach between the fields of epilepsy and cardiovascular sciences represents a novel and unprecedented opportunity in the field of epilepsy research and specifically in the area of SUDEP.

  CURE
Faingold
CURE
Uteshev

Carl Faingold, PhD & Victor Uteshev, PhD - Southern Illinois University School of Medicine / Carbondale, IL

SUDEP Prevention - Experimental Serotonergic Mechanisms in DBA/2 Mice

Sudden unexpected death in epilepsy (SUDEP) results from breathing failure after seizures. The DBA/2 mouse model also shows seizures and death due to breathing failure. Fluoxetine, a drug which increases the brain chemical serotonin, prevents breathing failure in DBA/2 mice. This collaborative project between Dr. Faingold, an epilepsy researcher and Dr. Utsehev-Gaard, a basic neuroscientist, will determine if novel drugs acting on serotonin will block SUDEP in DBA/2 mice with lower doses and fewer side effects. They will also examine how these drugs act on a brain region (solitary tract nucleus), which controls breathing to observe the nature of the defect causing death in DBA/2 mice.

  CURE
Ba
CURE
Rubenstein

Scott Baraban, PhD & John Rubenstein, MD, PhD - University of California/ San Francisco, CA

Award RHODE ISLAND AWARD

GABA progenitor cells as a treatment of epilepsy disorders

Transplantation of neuronal progenitor or “stem cells” offers great promise for developing an epilepsy cure. Because transplanted progenitors can migrate and integrate as new neurons in the host brain, manipulation of these cells could be a powerful means to stop seizures before they start. Dr. Baraban’s lab has developed a method to transplant embryonic progenitor cells that integrate exclusively as inhibitory interneurons. In a parallel study, they developed a mouse mutant characterized by interneuron loss, reduced inhibition and late-onset epilepsy. Combining the expertise of Dr. Baraban, an established epilepsy investigator and Dr. Rubenstein, a world-expert on interneuron development, this CURE study will combine these two projects into a critical “proof-of-principle” trial aiming to determine whether transplanted GABA-progenitor cells restore normal levels of inhibition and rescue these mutant mice from developing epilepsy. This study is a necessary next step toward development of appropriate clinical treatments utilizing progenitor cells.

CURE Grantee Finds Cell Transplantation Holds Promise for Epilepsy

  CURE
Blendy
CURE
Porter

Julie Blendy, PhD, University of Pennsylvania, Philadelphia, PA & Brenda Porter, MD - Children’s Hospital of Philadelphia, Philadelphia, PA

award 2007 NORTHWESTERN DANCE MARATHON AWARD

The Role of CREB in Epileptogenesis

The goal of this project is to identify cellular and molecular changes that contribute to the development of epilepsy after an injury to the brain. A large number of molecular, cellular and physiologic changes have been described following brain injury, including neuronal cell loss, and changes in the expression of genes and proteins. Dr. Porter, an epilepsy researcher, and Julie Blendy, a pharmacologist will examine whether one of the master regulators of neuronal survival and gene expression, CREB, is necessary for animals to develop epilepsy after brain injury.

  CURE

Douglas Nordli, MD - Children’s Memorial Hospital, Chicago, IL
In collaboration with: William Gaillard, MD – George Washington University Medical School, Washington, DC & Helen Cross, MD, PhD – Great Ormond Street Hospital for Children, London England

Pediatric Epilepsy Database Consortium

Dr. Nordli is leading an effort to create a database consortium of pediatric epilepsy centers. The centers, in Chicago, Washington, DC, and London, accumulate and track standardized information about children with epilepsy. Data are collected from medical charts, deidentified, and entered into a secure web-based database. By collecting and sharing the medical histories of a large number of children with epilepsy, it is hoped that treatment for those with difficult-to-treat epilepsy can be greatly improved. Dr. Nordli’s team hopes to learn which patients go into remission, and what medications may have aided in recovery. In addition, the consortium will provide the data for comparative clinical studies to help all children with epilepsy.

2007 Challenge Awards

Carmant

Lionel Carmant, MD - CHU-Sainte-Justine, Montreal, Canada

Preventing Autism and Other Long-term Complications of Infantile Spasms (IS)

Infantile spasms are a catastrophic form of epilepsy, because they are associated with an arrest or even a regression in the physical and mental development of children affected. More than 80% of children become mentally retarded and more than 10% develop autistic behaviors. In previous studies, children received a standard protocol of vitamin B6 and high dose vigabatrin for six months, except those with persistent spasms or EEG abnormalities at two weeks, who administered high dose steroids. In addition, in a double-blind manner, children received the neuroprotective treatment (flunarizine) versus placebo. In this two year study, Dr. Camant will evaluate whether this neuroprotective treatment improved long-term outcome by performing a developmental evaluation at 24 months and another one at 30 months post-diagnosis for autism. If preliminary results prove to be correct, Carmant anticipates that children treated with flunarizine will be more likely to develop normally and less likely to develop autism.

  CURE
D'Arcangelo

Gabriella D’Arcangelo, PhD - Rutgers University, Piscataway, NJ

award JULIE'S HOPE AWARD (partial scholarship)

Generation and Characterization of Mouse Models of Cortical Dysplasia

Epilepsy affects approximately one in every 100 children, and over 30% of these patients cannot be controlled with traditional antiepileptic treatments. Many of these children are found to have malformations of the cerebral cortex (cortical dysplasia).  As a first step towards finding a cure for this type of epilepsy Dr. D’Arcangelo will create genetically engineered mice as animal models for cortical dysplasia.  This new mouse model will be based on the abnormal activation of the PI3K signaling pathway in dysplastic brain cells. In this three year study, the model will be used to test the effectiveness of specific inhibitors of this pathway which will potentially lead to new antiepileptic agents.

  CURE
   

2007 Quest Awards

Poolos

Nicholas Poolos, MD, PhD - University of Washington / Seattle, WA

award THE MATTHEW SIRAVO MEMORIAL AWARD

Kinase Mediation of Antiepileptic Drug Action

Many of the antiepileptic drugs (AEDs) in clinical use today have mechanisms of action that remain unclear. One AED in particular, lamotrigine, appears to lack a direct action on the ion channel (the HCN channel) that may be responsible for its effectiveness across a broad spectrum of seizure types. Dr. Poolos will investigate the novel hypothesis that lamotrigine may regulate HCN channels not by direct interaction, but instead by altering the behavior of intracellular enzymes (kinases) that in turn control ion channel activity. If this hypothesis is proven, it will suggest new pathways for development of improved drugs against epilepsy.

  CURE
Godwin

Dwayne W. Godwin, PhD - Wake Forest University School of Medicine / Winston-Salem, NC

award THE CURE 365 AWARD

Metabotropic Glutamate Receptors - a Strategic Target for Novel Antiepileptic Therapeutics

Epilepsy is a chronic neurological disorder characterized by seizures that involve specific systems of the brain in the case of partial seizures, or seizures that may start in a restricted region of the brain but spread, or generalize, to involve other regions. Glutamate is the predominant excitatory neurotransmitter in the brain, and has a fundamental role in the communication of activity, whether that activity is normal or abnormal. Dr. Godwin’s research is focused on a class of glutamate receptors called metabotropic glutamate receptors. These receptors modulate the release of glutamate, and can selectively suppress hyperactive synapses. Dr. Godwin  plans to  strategically target a specific type of metabotropic receptor that reduces glutamate release at the key sites in the brain where seizures start and spread. By taking advantage of selective pharmacological agents, he hopes to stop or impede the generation of seizures before they start. The modulatory nature of these targets may provide new pharmacological treatment options with fewer side effects than are observed in currently prescribed anti-epileptic drugs, and may be helpful to individuals whose seizures may be resistant to current treatments.

  CURE
Soul

Janet Soul, MD, CM - Children’s Hospital Boston and Harvard Medical School/ Boston, MA

award THE GRAHAM GODDARD YOUNG INVESTIGATOR AWARD (sponsored by an unrestricted educational grant from UCB Pharma)

Pilot Study of Bumetanide For Refractory Neonatal Seizures

Newborn babies have seizures much more frequently than either children or adults, and their seizures are often associated with serious long-term consequences such as epilepsy, learning disabilities and cerebral palsy. Although newborn seizures are very common, medications currently used to treat them are relatively ineffective and may have serious side effects.  A medication called bumetanide shows great promise for treating newborn seizures because the drug blocks special channels present only in the brain cells of newborns. We will conduct a pilot trial to determine whether bumetanide is a safe drug for the treatment of newborn seizures.

  CURE
   

Due to a change in CURE's funding cycle, two rounds of grants were awarded this year.

2007 CURE Award Grantees

Kubek

Michael J. Kubek, PhD - Indiana University School of Medicine, Indianapolis, IN

award RHODE ISLAND AWARD

Intranasal delivery of sustained-release anticonvulsant neuropeptide nanoparticles in seizure therapy

A new class of brain-derived compounds known as anticonvulsant neuropeptides has emerged after years of basic and clinical research. Unfortunately, delivering such neuropeptides to treat epilepsy has been difficult because of their inability to access the brain. The goal of this Dr. Kubek’s research is to develop a neuropeptide-containing nanoparticle nasal spray for seizure therapy. The hope is that this research will lead to a new treatment for seizure prevention and ultimately a cure for seizure disorders.

  CURE
Murphy
CURE
Parent

Geoffrey Murphy, BS, PhD and Jack Parent, MD - University of Michigan, Ann Arbor, MI

Functional Integration of Ectopic Granule Cells in a Rat Model of TLE

Mesial temporal lobe epilepsy (mTLE) is a common epilepsy syndrome that is typified by seizures that are unresponsive to anticonvulsant drugs and often requires surgical intervention. Current medications are solely directed at seizure management and do nothing to treat the underlying disease. Therefore, the experiments in this proposal are focused on the early events that occur during the development of epilepsy. In addition to providing critical insight into the basic mechanisms that contribute to the development of epilepsy, these preclinical studies may lead to novel therapies directed at preventing the development of epilepsy after brain insults.

  CURE
Potschka

Heidrum Potschka, DVM - Ludwig-Maximilians-University, Munich, Germany

Validation of New Strategies to Overcome Pharmacoresistance of Epilepsy Based on Multidrug Transporter Overexpression

Several studies indicate that local overexpression of multidrug transporters in the epileptogenic tissue limits access of antiepileptic drugs to their target sites, thereby contributing to pharmacoresistance. The aim of Dr. Potschka's project is to test whether resistance can be overcome by downregulating the expression of the major multidrug transporter P-glycoprotein by RNA interference (RNAi). As a second strategy intranasal administration of antiepileptic drugs will be tested as a means to bypass the blood-brain barrier and to achieve sufficient brain delivery.

  CURE
Rho

Jong M. Rho, MD - Barrow Neurological Institute, Phoenix, AZ

A Planar Multi-Electrode Array Analysis of Surgically Resected Human Hypothalamic Hamartoma Tissue

The hypothalamic hamartoma (HH) is a rare congenital brain tumor that produces unusual "laughing" seizures, which typically do not respond to medications, and is associated with cognitive and hormonal abnormalities. The major goal of this study is to evaluate brain slices prepared from human surgical specimens using a highly computerized multi-electrode recording technique, one that may provide clues as to how seizures begin and spread within the tissue, and subsequently determine if any currently available drugs can block the abnormal firing of HH cells. This information may provide an immediate treatment option for HH patients, and for patients with other forms of epilepsy, this research may find important clues to how seizures may occur deep within the brain.

CURE
White
CURE
Fujinami

H. Steve White, Ph.D. and Robert S. Fujinami, Ph.D. - University of Utah, Salt Lake City, UT

award 2007 CENTRAL NEW YORK AWARD, In memory
of Christopher Donalty and Kyle Coggins

Theiler's virus-induced encephalopathy: a novel model of viral-induced epilepsy

Viral infections of the CNS are associated with an increased risk for the development of epilepsy. At the present time, there is no animal model that accurately reproduces the pathology and physiological features of human virus CNS infection (encephalitis)-induced epilepsy. The purpose of this study is to characterize the clinical and electrographic seizure phenotype, determine virus-immune-CNS parameters involved in seizure development and seizure susceptibility and assess the impact of acute viral infection on seizure threshold and the development of epilepsy. The planned investigations will help to establish a new animal model of viral CNS infection that can be utilized for identifying novel therapies that would prevent the development of encephalopathy-induced epilepsy.

  CURE
Kang

Jingqiong Kang, MD, PhD - Vanderbilt University Medical Center, Nashville, TN

award THE MAGGIE LOEFFEL AWARD

Aberrant trafficking of GABAA receptor epilepsy mutations leads to endoplasmic reticulum stress-related neurodegeneration following prolonged febrile seizures

It has been demonstrated that prolonged febrile seizures – seizures with high fever – may lead to atrophy in the hippocampal region of the brain, resulting in the development of partial complex epilepsy. The pathological basis for the atrophy is unclear, but a common genetic basis between febrile seizures and the later development of epilepsy is suspected. This project seeks to understand the role of a particular epilepsy gene mutation (GABAA receptor subunits) in this process. Findings from this study could ultimately lead to novel approaches to treatment and prevention in patients at risk of developing epilepsy after febrile seizures.

   
   

2007 Traumatic Brain Injury Grantees

CURE

Raimondo D'Ambrosio, PhD - University of Washington, Seattle, WA

Prophylaxis of posttraumatic epilepsy following head injury in the rat

Posttraumatic epilepsy is a chronic neurological disorder that appears following head injury and for which there currently is no prophylactic treatment. This project aims to achieve two goals by employing our recently developed model of posttraumatic epilepsy, in which chronic recurrent spontaneous partial seizures reliably appear in the rat following a realistic insult (FPI) presenting mechanical features very similar to human closed head injury. First, we aim to examine acute and subacute electrocorticograms to determine whether an electrophysiological biomarker of epileptogenesis exists that would allow one to predict the later onset of epilepsy. Such a biomarker would allow one to target antiepileptogenic treatments to patients at risk of developing epilepsy and not to others, therefore reducing side effects. Second, we aim to begin testing the effectiveness of drugs that already have an excellent human safety profile and that are currently being considered for clinical trial of antiepileptogenesis following head injury. Our work will help optimize these clinical trials and increase their chances of success.

  CURE
McNamara

James O. McNamara, MD
Xiao-Ping He, MD, PhD, and Bradley Kolls, MD, PhD, co-investigators - Duke University Medical Center, Durham, NC

Mouse Model of Post-traumatic Epilepsy

Post-traumatic epilepsy (PTE) is a major public health problem for both civilians and soldiers, accounting for approximately 20% of symptomatic epilepsy. Research into the mechanisms of this disease has lagged due to the lack of a useful animal model. The goal of this work is to develop a closed head injury model of PTE in a mouse strain that is amenable to genetic manipulation. This will facilitate elucidating the molecular mechanisms of post-traumatic epileptogenesis and lead to effective preventative therapy.
  CURE
Nedergaard

Maiken Nedergaard, MD, PhD - University of Rochester, Rochester, NY

Post traumatic epilepsy – targeting reactive gliosis

This project offers a new conceptual and operational approach to understanding the cellular basis of seizure disorders. If a dysregulation in astrocytic Ca2+ signaling indeed proves causal in epileptogenesis – as our data strongly suggest – then the implications of this new perspective to pharmacotherapy could be profound. The often imprecise correlation of anti-epileptogenic activity with synaptic suppression would be better understood, allowing new emphasis on therapeutic strategies intended to screen for agents able to suppress astrocytic Ca2+ signaling and/or glutamate release.

  CURE
Pitkanen

Asla Pitkänen, MD, PhD, DSci - University of Kuopio, Finland

Post-traumatic epileptogenesis: Development and use of animal models for identification of molecular mechanisms and surrogate markers

Traumatic brain injury (TBI) is a major cause of acquired focal epilepsy in adults. This projects aims at developing new, clinically relevant animal models that can be used to investigate molecular mechanisms of epileptogenesis after TBI and to test novel candidate treatments for prevention of post-traumatic epilepsy (PTE). The second goal is to find surrogate markers that could identify the subjects who are at risk of developing PTE by using magnetic resonance imaging.

  CURE
Smyth

Matthew Smyth, MD - Washington University, St. Louis, MO
Raimondo D'Ambrosio, PhD, co-investigator - University of Washington, Seattle, WA

Evaluation of focal cortical cooling to prevent epileptogenesis and control chronic seizures induced by fluid percussion injury in the rat

The aim of our proposal is to evaluate the effects of focal brain cooling on treating and preventing post-traumatic seizures. This proposal follows the initial discovery and description of electrical and behavioral partial seizures following fluid-percussion injury (FPI) in the rat. Focal brain cooling may provide a novel therapeutic model to treat medically refractory seizures without tissue destruction inherent in surgical resections and disconnections. Because of the similarities existing between this rodent model and human post-traumatic epilepsy (PTE), the data collected during this project will determine whether focal cooling may lead to improved therapy for acquired human epilepsy. The experiments planned include the administration of direct focal cooling at the FPI site after the development of post-traumatic chronic seizures in order to evaluate the anti-seizure effect of focal cortical cooling. Experiments also planned include the evaluation of the magnitude and extent of cooling on surrounding brain tissue, the temperatures required to inhibit seizure activity, and the potential neurotoxic effects of focal cooling. Obtaining these data will be an instrumental first step toward the translation of this technology in clinical settings.

  CURE
Scott

Scott Thompson, PhD - University of Maryland School of Medicine, Baltimore, MD

Preventing Denervation-induced Hyperexcitability After Traumatic CNS Injury

A traumatic brain injury causes several disorders that are characterized by the delayed occurrence of changes in brain function, such as posttraumatic epilepsy. Because brain injuries are complicated, we have developed a simplified experimental approach that allows us to look at one particular consequence of brain injury in isolation, namely the loss of normal input after nerve pathways are severed during an injury. We have evidence that the brain cells that lose their normal inputs try to compensate for the lack of normal activity. Unfortunately, that this ‘sensible’ response of the cells results in an unintended consequence- epilepsy. Using laboratory rats, we will be testing the mechanisms that the cells use to compensate for the lack of activity and also test a class of medicines that may counteract those changes. We hope that our work will lead to novel treatments that can prevent the development of epilepsy after brain injury. 

   
   

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2006 CURE Award Recipients

cure epilepsy

Tracy Butler, MD - Weill Medical College of Cornell University, New York, NY

Imaging Neuroinflammation in Focal Epilepsy

Inflammation, a vital process by which dead or damaged tissue is broken down, can be harmful when excessive or prolonged.  This project will use Positron Emission Tomography (PET) scanning to examine inflammation in the brains of patients with uncontrolled focal epilepsy. This could prove helpful in planning for epilepsy surgery and may lead to the development of new strategies, including use of anti-inflammatory agents to treat and prevent epilepsy. 

cure epilepsy
cure epilepsy

Vittorio Gallo, PhD - Children’s National Medical Center & George Washington University, Washington DC

Regeneration of Hippocampal Neurons in Mesial Temporal Lobe Epilepsy

The goal of this proposed project is to develop a new approach to curing mesial temporal lobe epilepsy (MTLE), one of the most commonly recognized forms of childhood-onset epilepsy. This study will investigate the transfer of progenitor cells to replace inhibitory neurons lost in patients with temporal lobe epilepsy as a means of re-establishing normal function.
cure epilepsy
cure epilepsy

Michael Kubek, PhD - Indiana University School of Medicine, Indianapolis, IN

Intranasal Delivery of Sustained-release Anticonvulsant Neuropeptide Nanoparticles in Seizure Therapy

Certain neuropeptides may be effective in inhibiting seizures. Unfortunately, there are challenges associated with developing neuropeptides for use by patients with epilepsy. This project will explore the use of an intranasal delivery of neuropeptide nanoparticles for seizure therapy. Positive results of this project could lead to new directions for epilepsy therapy, prevention and ultimately a cure.

cure epilepsy
cure epilepsy

THE  FALK MEDICAL RESEARCH TRUST AWARD

Heidrun Potschka, DVM - University of Veterinary Medicine, Hannover, Germany

Validation of New Strategies to Overcome Pharmacoresistance of Epilepsy Based on Multidrug Transporter Overexpression

Several genetic studies point toward a specific genetic abnormality (the overexpression of multidrug transporters) in patients with epilepsy whose seizures do not respond to medications. The first goal of this project is to test whether modifications in that gene might help these patients better respond to medications.  In addition, intranasal delivery of antiepileptic drugs will be tested as a means of bypassing the blood-brain barrier to achieve sufficient delivery of medications directly to the brain. 

cure epilepsy
cure epilepsy

THE CHRISTOPHER DONALTY INTERDISCIPLINARY RESEARCH AWARD

Jenna L. Rickus, PhD and Pedro L. Irazoqui, PhD - Purdue University, West Lafayette, IN

A Hybrid Cellular-Silicon Neural Prosthetic for Epilepsy

The major treatment problems facing patients with epilepsy are resistance to drugs and unwanted side effects. Targeting treatment to a specific area of the brain immediately prior to and during a seizure would present a significant advancement. The goal of this project, which melds biology and engineering, is to develop a novel, cell-based neural prosthetic to electrically detect a seizure before it occurs and respond by stimulating transplanted cells to rapidly release GABA (a critical therapeutic target in epilepsy), thereby preventing the seizure.

  cure epilepsy
cure epilepsy

THE GRAHAM GODDARD AWARD
(sponsored by an unrestricted educational grant from UCB Pharma)

Alexander Rotenberg, MD, PhD - Boston Chidren’s Hospital, Brookline, MA

Transcranial Magnetic Stimulation: Anticonvulsant and Antiepileptic Properties

Transcranial magnetic stimulation (TMS) can potentially be used to interrupt ongoing seizure activity, prevent epilepsy after an event such as status epilepticus, and increase seizure-free periods. Yet, TMS is in the early stages of development, and the field would benefit from the use of animal models to evaluate whether seizures can be shortened with this technique and whether TMS can protect against the development of chronic epilepsy. This study will examine the utility of TMS in a rat model of epilepsy. The results will guide the use of TMS in patients with epilepsy and the prevention of epilepsy in those patients at risk. 

  cure epilepsy
cure epilepsy

THE MAGGIE LOEFFEL AWARD

Walter M. St.-John, PhD - Dartmouth Medical School, Lebanon, NH

Seizures and Respiration – A Possible Basis for SUDEP (Sudden Unexplained Death in Epilepsy)

Although seizure-induced changes in breathing and/or in the function of the heart have been proposed as the cause for this devastating consequence of epilepsy, much research still needs to be done. This investigator will categorize changes in breathing during seizures and describe how these changes might be responsible for SUDEP.

  cure epilepsy
cure epilepsy

THE RHODE ISLAND AWARD

Nikolaus J. Sucher, MD – Children’s Hospital & Harvard Medical School, Boston, MA

A role for the mTOR Pathway in NMDA Receptor Mediated Epileptogenesis: a Molecular Investigation of Protein Interactions

The NMDA receptor is crucial for the normal function of the brain. The receptor is a protein complex that is composed of multiple subunits, some of which may be critical for the development of epilepsy in patients with Tuberous Sclerosis (TSC). This study will investigate the molecular details of the interaction and function of selected proteins, which may suggest novel targets for the treatment of TSC and epilepsy.

   

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2005 Grant Recipients

HOPE FOUNDATION
Controlling Epileptogenicity in Human Focal Cortical Dysplasia

Massimo Avoli, MD, PhD
Montreal Neurological Institute and Departments of Neurology & Neurosurgery, McGill University / Montreal, PQ, Canada Dipartimento di Fisiologia Umana e Farmacologia, Università di Roma "La Sapienza" / Rome, Italy

Focal Cortical Dysplasia (FCD) is a structural abnormality in the brain, which can lead to seizures, which do not respond to pharmacological treatment. In a second year of CURE funding, Dr. Avoli will be testing the hypothesis that gap-junctions in patients with FCD contribute to seizures and whether repetitive electrical stimulation of FCD networks can prevent seizures.

cure
RHODE ISLAND AWARD
Identification of Potential Gene Targets for Cortical Dysplasia

Gabriella D’Arcangelo, PhD
Baylor College of Medicine / Houston

This study will conduct a molecular characterization of the abnormal neurons found in brain tissue resected from patients with focal cortical dysplasia (FCD). Gene expression profiles of abnormal neurons will be generated using cutting edge technologies such as laser capture microdissection and microarray analysis. This research will provide the necessary groundwork for designing future studies aimed at reducing or eliminating seizures in cortical dysplasia patients.
cure

FALK FOUNDATION
Developmental Phenotype of Seizure-Prone Mice

Stephen C. Heinrichs, PhD
Boston College Department of Psychology

In a mouse model of epilepsy, Dr. Heinrichs will examine the role of parental care during early development in halting or delaying the onset of seizures. Better understanding of the importance of early environment could allow for the design of non-drug interventions, which could potentially be used in children who are at risk of developing epilepsy.


Pathogenesis of Cortical Lesions in a Model of Tuberous Sclerosis

Arnold R. Kriegstein, MD, PhD
University of California, San Francisco

Sixty to ninety percent of patients with tuberous sclerosis have difficult to control epilepsy due to genetically abnormal progenitor cells, which hamper proper cortical development. In this study, observation of the proliferation and migration of these cells will add valuable insight into how these gene defects influence cortical development and on potential new therapies.
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THE MAGGIE LOEFFEL AWARD
Development of Novel Antiepileptic Drugs

Edward Perez-Reyes, PhD
University of Virginia

Mutations in certain genes may be responsible for hyperexcitability in the brain. A specific T channel gene has been associated with childhood absence epilepsy, a type of epilepsy in which the child exhibits staring spells during which he or she is unaware and unresponsive. Dr. Perez-Reyes strives to develop a T-type channel blocker as a novel anti-epileptic medication, which can be used in significantly lower doses to substantially reduce debilitating treatment side effects for these children.

cure

HOPE FOUNDATION
Gene Expression in Cortical Dysplasia

Brenda E. Porter, MD, PhD
Children’s Hospital of Philadelphia

Many children with hard to treat epilepsy have an abnormality called focal cortical dysplasia (FCD) in which, during brain development, neurons become disorganized and misalign. This study tries to understand which molecules in the cortical dysplasia neurons are different and how these differences cause epilepsy. The long term aim is to investigate possible means of “turning off” the cortical dysplasia neurons in the hope of fulfilling CURE’s goal of no seizures/no side effects.


Molecular Mechanism of Limbic Epilepsy in a New Genetic Mouse Model

Yan Yang, PhD
The Jackson Laboratory / Maine

Mouse models of epilepsy have contributed to the discovery of human epilepsy genes and all antiepileptic drugs to date. Dr. Yang has identified a new gene (BRUNOL4), which plays a role in a type of epilepsy originating in the temporal lobe. He will investigate how a deficiency in this gene leads to recurrent seizures in mice, and evaluate novel anti-epileptic therapies using this new mouse model of epilepsy.

 

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2004 Grant Recipients

Development of Novel Epilepsy Treatments Utilizing Embryonic Progenitor Cells

Scott C. Baraban, PhD
University of California, San Francisco

The aim of Dr. Baraban’s project is to investigate whether stem cells transplanted into the central nervous system of mice can alter synaptic function in the brain, change the overall level of excitability in the brain and act as a “cure” for patients with uncontrollable epilepsy.

Therapeutic Efficacy of Environmental Enrichment Following Early-life Seizures

Sookyong Koh, MD, PhD
Children’s Memorial Hospital / Northwestern University

The potential of an intense educational program as a therapeutic tool for children with epilepsy has received very little attention, though it is believed to be effective for other neurological disorders. There is currently no effective intervention for children with epilepsy to prevent the long-term brain damage and neurological effects of seizures. The goal of Dr. Koh’s project is to study, in young rats, the effectiveness of environmental enrichment in reversing seizure-induced brain damage.

Specific Immunotherapy for epilepsy via GluR3B peptide oral vaccination or anti-GluR3B peptide antibodies administration

Vivian I. Teichberg, PhD
Weizmann Institute of Science, Israel

In the last few years, immunotherapy has emerged as a possible treatment for diseases of the central nervous system, including epilepsy. Dr. Teichberg is investigating the scope and efficacy of vaccination against a particular AMPA receptor in epilepsy. This is an important preliminary look at the potential of vaccination in epilepsy as a means of achieving ‘no seizures-no side effects’.

Neuroprotective Effects of b-estradiol on seizure-induced hippocampal damage

Jana Veliskova, MD, PhD
Albert Einstein College of Medicine / Bronx, NY

Temporal Lobe Epilepsy is one of the most common forms of epilepsy, and often results in loss of neurons in the hippocampus of the brain, which subsequently leads to an increase in seizures. Dr. Veliskova’s study is examining, in female rats, the effectiveness of lowdose b-estradiol in protecting against damage to the hippocampus and the resulting increase in seizures.
THE CHRISTOPHER DONALTY MEMORIAL AWARD
Prevention of Sudden Death in Epilepsy

Carl L. Faingold, PhD
Southern Illinois University School of Medicine

Sudden Death in Epilepsy (SUDEP) accounts for 5-17% of deaths in patients with epilepsy, including children. The aim of this proposal is to understand what brain abnormalities cause animals to be susceptible to SUDEP and determine if blocking the action of certain naturallyoccurring brain chemicals can prevent sudden death in those animals.

THE FALK MEDICAL RESEARCH TRUST AWARD FOR 2004
Polyunsaturated Fatty Acids for Treatment of Refractory Epilepsy

Edward B. Bromfield, MD
Brigham and Women’s Hospital / Boston

The objective of Dr. Bromfield’s study is to determine whether polyunsaturated fatty acids can be used safely and effectively to treat epilepsy. Fatty acids have been shown to protect against seizures in animal models, and there is some evidence of the same effect in humans. This is the first controlled, double-blind trial in humans, and will provide the foundation for a larger multicenter trial if efficacy, safety and tolerability are confirmed.

THE GRAHAM GODDARD AWARD (SPONSORED BY AN UNRESTRICTED GRANT FROM UCB PHARMA)
Identification and evaluation of neuroprotective genes in the primed pilocarpine model

Karin Borges, PhD
Emory University

Epilepsy is strongly correlated with the death of neurons in the brain. Protecting neurons seems to be a promising strategy to inhibit the development of severe epilepsy. In a mouse model of epilepsy, Dr. Borges will identify and evaluate genes involved in the brain’s own protective mechanisms for their ability to inhibit the development of epilepsy. This could potentially aid in identifying new biochemical pathways leading to new drug targets which could limit neuronal injury and the development of epilepsy.
THE MAGGIE LOEFFEL AWARD
High frequency epileptiform oscillations in extratemporal epilepsy

Gregory A. Worrell, MD, PhD
Mayo Clinic / Rochester, MN

Advances in epilepsy surgery and the advent of implantable brain devices which predict the onset of seizures and administer treatment, require greater accuracy in pinpointing the exact location where seizures begin. Dr. Worrell’s study of the usefulness of high-frequency epileptiform oscillations to more accurately locate the area of the brain involved in the seizure, is a unique collaboration combining the neuroengineering strength of the University of Pennsylvania with Mayo Clinic’s large surgical epilepsy practice, translating engineering advances into clinical practice.


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2003 Grant Recipients*

Controlling Epileptogenicity in Human Focal Cortical Dysplasia
Massimo Avoli, MD, PhD. Montreal Neurological Institute and Departments of Neurology & Neurosurgery, McGill University / Montreal, PQ, Canada Dipartimento di Fisiologia Umana e Farmacologia, Università di Roma "La Sapienza" / Rome, Italy

Ion Channel Mutations in Inherited Epilepsy
Andrew Escayg, PhD. Emory University

Can Preemptive Low Frequency Stimulation Decrease the Incidence of Kindled Seizures?
Jeffrey H. Goodman, PhD. Center for Neural Recovery and Rehabilitation Research, Helen Hayes Hospital

Potassium Channel Viral Vector Treatment for Epilepsy
Philip A. Schwartzkroin, PhD. University of California, Davis

*Pending Final Contract Approval


2002 Grant Recipients

Early Detection and Minimal Perturbation for Seizure Control
Peter L. Carlen, MD, FRCP Toronto Western Research Institute

Drug Application to the Seizure Focus
Robert Fisher, MD, PhD Stanford University

Suppression of the Epileptic Focus by Intracerebral Injections of Tetrodotoxin-Loaded Microparticles
Gregory Holmes, MD Harvard University

Cortical Magnetometabolic Mapping of Focal Epileptogenic Malformations of Development
Ruben Kuzniecky, MD University of Alabama at Birmingham

Targeting Inflammatory Cytokines for Controlling Seizures
Annamaria Vezzani, PhD Mario Negri Institute Milan, Italy

Proinflammatory cytokines and related inflammatory and anti-inflammatory molecules are highly expressed in the brain shortly after seizures induced in experimental animals. Their expression in CNS is larger and more widespread when seizures are associated with neuronal damage.

Inflammatory cytokines such as interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha) modulate seizures. In particular, we found that IL-1beta has proconvulsant activity while its endogenous receptor antagonist (IL-1Ra) mediates potent anticonvulsant actions in various models of limbic seizures. This evidence suggests the novel concept that the ratio between IL-1Ra/IL-1beta in the brain is crucial for the occurrence of seizures.

Our present goal focuses on the possibility to control seizures in epilepsy by targeting cytokines, in particular the IL-1 and TNF-alpha systems.

This is a novel approach that takes advantage of the ample choice of pharmacological means to affect cytokines’ actions. The expression of cytokines in the brain is constitutively very low strongly suggesting their limited role in normal brain physiology. This property reduces the chances of nerological side-effects when acting on cytokines. Indeed, some of these molecules have been already used in humans for curing peripheral inflammatory diseases such as septic shock and rheumatoid arthritis. In particular, therapies targeting IL-1 and TNF-alpha appear to be well tolerated in humans even when used at relatively high doses.

IL-1 system. We will attempt to increase the endogenous levels of IL-1Ra in the brain by systemic or intracysternal delivery of drugs or viral vectors carrying the IL-1Ra gene to assess if this results in efficacious seizure control as after IL-1Ra intracerebral injection. We will attempt to inhibit seizures by decreasing seizure-induced production of IL-1beta using caspase-1 inhibitors or impairing second messenger systems crucially involved in the functional action of IL-beta.

TNF-alpha system. Since intracerebral application of TNF-alpha decreases limbic seizures in mice (see our preliminary results), we plan to investigate which receptor subtypes mediate this anticonvulsant action using transgenic and knock-out mice.

To study the functional role of newly synthetized brain inflammatory and anti-inflammatory molecules in the pathophysiology of seizures may lead to the characterization of novel targets for developing antiepileptic pharmacological treatments with reduced side-effects.

Effects of Photodynamic Therapy on Seizures in the Rat Kindling Model of Epilepsy
Edie Zusman, MD UC Davis


2001 Grant Recipients

Early Detection and Minimal Perturbation for Seizure Control
Peter L. Carlen, MD, FRCP Toronto Western Research Institute Toronto, Ontario, Canada

Developing a Cure for Lafora's Progressive Myoclonus Epilepsy
Antonio V. Delgado-Escueta, MD UCLA & Greater Los Angeles VA Medical Center Los Angeles, California

Glial Function in a Chronic Model of Epileptic Excitability
Adriana Emmi, MD, PhD University of Washington Seattle, Washington

Intraoperative Optical Mapping of Human Neocortical Epilepsy in the Treatment of Partial Onset Seizures
Theodore H. Schwartz, MD Weill Medical College of Cornell

Focal Cooling as a Therapy for Neocortical Epilepsy
Steven M. Rothman, MD Washington University School of Medicine St. Louis, Missouri

Anticonvulsant Effects of Substantia Nigra Stimulation
Libor Velisek, MD, PhD Albert Einstein College of Medicine Bronx, New York


2000 Grant Recipients

Anticonvulsant Effects of Substantia Nigra Stimulation
Libor Velisek, MD, PhD Assistant Professor Albert Einstein College of Medicine, Bronx, NY

Autoantibodies in Acquired vs. Genetic Variants of Pediatric Epilepsy
Michael G. Chez, MD Lake Forest, IL

 

 

See previous years' CURE grant recipients:
2013  |  2012  |  2011  |  2010  |  2009  |  2008  |  Older

 

CURE For questions, please contact Julie Milder at the CURE office, 312.255.1801, or email julie@cureepilepsy.org.

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