CURE Grant Recipients

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

2010 Research Awards

Challenge Awards
Two- to three-year grants for established investigators

The Brighter Future Award
In honor of Lauren Axelrod, funded by a caring donor
	Gary Yellen, PhD and Nika Danial, PhD Harvard Medical School; Dana-Farber Cancer Institute “Seizure Resistance through Metabolic Control in Novel Mouse Model” Nearly one-third of people with epilepsy have seizures that cannot be well-treated by existing medications. The success of dietary treatment (such as the ketogenic diet) for many of these individuals suggests a powerful connection between metabolism and seizures. However, these diets are difficult to maintain, spurring a search for alternative ways to manipulate metabolism in order to prevent seizures. Drs. Danial and Yellen are collaborating on a multi-disciplinary approach to this problem based on an exciting initial observation. They found that a genetic manipulation in mice that reduces the metabolism of glucose (sugars) and enhances the metabolism of ketone bodies (compounds which are a vital source of energy in the brain during fasting) can produce strong seizure resistance, which is far more dramatic than seen with the ketogenic diet. They will explore the mechanism of this effect and investigate novel therapeutic targets and approaches for epilepsy treatment.

The 2010 Falk Medical Research Trust Award

Steven Roper, MD University of Florida “Treating Cortical Dysplasia with Adult Human Neural Progenitor Cells” Cortical dysplasia (CD) is a problem of brain development that often causes severe epilepsy. Using an animal model of CD, Dr. Roper and his collaborators will use a novel approach to the treatment of epilepsy in CD using adult human neural progenitor cells from surgically removed tissue from individuals with intractable epilepsy. These cells will be put into rats with CD in order to replace the lost inhibitory neurons and restore normal brain function. This project offers a new direction for treatment of intractable epilepsies using targeted cellular therapies. If this research is successful, the use of adult human donor cells will facilitate the translation of this approach to treatments for individuals with epilepsy due to CD.

Prevention of Epilepsy After Brain Injury Award
Two- to three-year grants in support of research preventing or treating post-traumatic epilepsy

The Friends for a Cure Award
This grant was funded by donations made for CURE’s fall 2009 Every Dollar Counts campaign.
	Istvan Mody, PhD UCLA School of Medicine “Prevention of post-stroke epileptogenesis” Cerebrovascular brain injuries (including stroke and ischemia) account for 11% of the symptomatic epilepsies and the incidence of epilepsy after a stroke can be as high as 20%. Dr. Mody has developed a novel and specific cerebrovascular trauma model in mice that reduces the blood supply to brain areas heavily involved in the genesis of epilepsy, and has preliminary data consistent with the development of epilepsy after such trauma. His investigation will focus on understanding the mechanisms leading to the development of epilepsy after the cerebrovascular injury, and on developing novel pharmacological approaches aimed at stopping the transition from stroke to epilepsy in its tracks.

Multidisciplinary Award
Two- year grants in support of collaborative research

The Heldman Award

Amy Brooks-Kayal, MD and Shelley Russek, PhD University of Colorado Denver/The Children's Hospital; Boston University School of Medicine “JaK/STAT inhibition to prevent epilepsy development and progression” Drs. Brooks-Kayal and Russek will examine the role of an important cell signaling pathway called the Jak/Stat pathway in the development and progression of epilepsy. Their labs recently discovered that this pathway regulates brain inhibition and is activated by seizures, likely in response to an increase during seizures of the growth factor, brain derived neurotrophic factor (BDNF). Using a combination of studies in the laboratory and in animal models of epilepsy, they will use specific blockers of BDNF and the Jak/STAT pathway to reduce or prevent epilepsy development and/or progression.

SUDEP Awards
One-year grants in support of SUDEP research

CURE & Dravet Syndrome Foundation Research Award

Sebastian Maier, MD, PhD and Massimo Mantegazza, PhD University Hospital of Wuerzburg; IPMC, Nice-Sophia Antipolis, France “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 in a model of Dravet syndrome in order to investigate the occurrence and mechanism of arrhythmias and their possible involvement in SUDEP.

The Leisher Family Award

Torbjorn Tomson, MD, PhD and Peter Mattsson, MD, PhD Karolinska Institutet; Uppsala University “Role of pharmacological treatment in the prevention of SUDEP” Drs. Tomson and Mattson will utilize three nation-wide Swedish registries that offer unique opportunities to study the association between drug treatment and risk of sudden unexplained death in epilepsy (SUDEP). The medical records of living individuals with epilepsy will be compared to those with SUDEP with respect to use of antiepileptic drugs (AEDs) and other drugs to assess if the risk of SUDEP is related to non-adherence to prescribed AEDs, to any specific type of AED, and if concomitant use of other drugs such as some antidepressants could be protective. This study will provide essential information for the development of pharmacological treatment strategies to reduce the risks of and to prevent SUDEP.

The 2010 Christopher Donalty & Kyle Coggins Memorial Award for SUDEP Research

Carl Faingold, PhD Southern Illinois University School of Medicine “Prevention of SUDEP by Serotonergic Agents in DBA/1 Mice” Dr. Faingold has developed a new animal model of human sudden unexpected death in epilepsy (SUDEP), DBA/1 mice. These animals show generalized seizures and then stop breathing if not resuscitated, which is common in human SUDEP. They found that drugs that increase the level of a neurochemical (serotonin) in the brain will prevent SUDEP in these mice. The current study will examine if new drugs that have a more selective effect on serotonin will prevent the respiratory arrest that follows seizures in these mice.

2010 Innovator Awards
One-year grants in support of the exploration of a highly innovative new concept or untested theory that addresses an important problem relevant to epilepsy

Lionel Carmant, MD University of Montreal “A New Experimental Model of Rasmussen's Encephalopathy: Understanding its Pathophysiology” Rasmussen encephalitis (RE) is a rare but severe brain disorder that starts in childhood with seizures that become more and more frequent, as well as a progressive weakness of the affected side. The mechanisms of RE are still not well understood, even if some experimental data suggest an immune mediated disorder. By injecting RE patients’ blood cells into severely immunologically-compromised mice, we are able to induce seizures and produce pathological findings in the mouse brain similar to pathological lesions observed in children with RE. We can also use frozen blood cells from individuals with RE, making our strategy to understand the pathophysiology of RE even more feasible. Preliminary data shows that RE is mediated by the immune system, and that seizures are due to the release of inflammation products followed by an infiltration of white blood cells in the brain. The model we will use for this research will allow us to identify the cells responsible for RE and to precisely determine the role of the immune system in this rare disorder. In the future, we plan to utilize this model test to new therapeutic strategies for RE.

Manisha Patel, PhD University of Colorado, Denver “Treatment of Epilepsy with a Catalytic Antioxidant” The vast majority of epilepsy research is focused on channels and synapses and only a minority focuses on metabolic processes. Although anticonvulsant drugs remain frontline therapies for controlling epilepsies, the search for novel disease-modifying drugs is highly desirable to halt the devastating effects of chronic seizures. Catalytic antioxidants are small molecule mimics of the body’s own defenses that can efficiently remove reactive oxygen species and in the process, regenerate themselves. The goal of this project is to conduct a proof-of-principle study to determine if early treatment with a novel catalytic antioxidant prevents metabolic dysfunction and epilepsy in mice lacking a critical mitochondrial antioxidant.

Alexander Rotenberg, MD, PhD Children’s Hospital Boston/Harvard Medical School “Prevention of Post-Traumatic Epilepsy by Application of Ceftriaxone Acutely After TBI” Traumatic brain injury (TBI) often leads to epilepsy with a delay that can be weeks to months after the initial trauma. At the biochemical level, the process that leads to epilepsy after TBI is in part mediated by an excess of the excitatory neurotransmitter glutamate whose concentration rises sharply after injury. Ceftriaxone and similar antibiotics, independent of their antibacterial properties, can increase function and expression of the glutamate transport protein, GLT1, which may remove excess glutamate after injury. Accordingly, we propose to test a novel application of ceftriaxone, acutely after brain injury when the biochemical changes leading to post-traumatic epilepsy are first emerging. Specifically we propose to use the established rat lateral fluid percussion injury (LFPI) severe TBI model in a preclinical trial to test whether daily injection of ceftriaxone acutely after TBI can (1) enhance GLT1 function and limit glutamate accumulation after injury, (2) limit cell death and (3) reduce the likelihood of seizures after TBI. As ceftriaxone and similar compounds are already in wide use for antibacterial treatment, we anticipate that positive data from the proposed experiments can be rapidly translated to novel clinical trials.

2009 Traumatic Brain Injury Awards

“Prevention of Epilepsy After Traumatic Brain Injury”
A Partnership with the United States Army Medical Research and Materiel Command (USAMRMC)

Richard J. Staba, PhD University of California, Los Angeles “Pathological Electrical Brain Activity in Traumatic Brain Injury” Traumatic brain injury and its major, commonly resulting condition, posttraumatic epilepsy (PTE), are associated with significant functional disability. Currently, there is no way to predict who will develop PTE after brain injury, and no effective treatments to prevent it. Dr. Staba’s research uses direct brain recordings to characterize very fast electrical events called pathologic high frequency oscillations (pHFOs) that are believed to be responsible for the generation of epilepsy in the brain. His research will attempt to confirm that pHFOs underlie PTE. The long-term goal is to utilize pHFOs as a biomarker to screen new disease-modifying drugs in order to prevent PTE.

Raimondo D’Ambrosio, PhD University of Washington John Miller, MD, PhD University of Washington Jeffrey Ojemann, MD University of Washington Matthew Smyth, MD Washington University Steven Rothman, MD University of Minnesota “Focal Cooling as a Prophylactic Treatment for Post-traumatic Epilepsy” Seizures resulting from head injury often emanate from the specific portion of the brain that has been injured, resulting in what are called partial seizures. This type of seizure is often especially resistant to treatment and there is an urgent need for novel and more effective treatments. Dr. D'Ambrosio's project will determine whether focal brain cooling—cooling of the area of the brain responsible for the epilepsy—is an effective option to terminate seizures in both animals and humans. The planned experiments will define both the therapeutic window best suited to control and potentially prevent the partial seizures induced by head injury in an animal model, and the magnitude and extent of surface cooling needed to achieve a similar objective in humans. If successful, this work will provide the groundwork for the translation of focal cortical cooling from “bench to bedside” as a treatment for human epilepsy.

Stefan M. Lee, PhD University of Southern California “New Biometric Technology for “Just-In-Time” Delivery of Anti-Convulsants Following Traumatic Brain Injury” A significant and common consequence of traumatic brain injury is a selective loss of inhibitory nerve cells around the site of impact, resulting in focal seizures emanating from the areas of the brain that have been injured. Dr. Lee’s research will focus on a completely new approach for the treatment of focal epilepsy utilizing a smart-pump. The smart-pump will release an anti-epileptic drug to the brain as soon as epileptic activity is detected to stop the seizure before it can spread to other parts of the brain. This technology represents the future of selective and immediate drug delivery for seizures, with the potential of minimizing adverse side effects of medications.

Asla Pitkänen, PhD University of Kuopio, Finland “Prevention of Post-Traumatic Epilepsy (PTE) by Pharmacological Neurostimulation – A Preclinical Proof-of-Principle Study in a Rat Model of PTE” The signature wound of the wars in Iraq and Afghanistan is traumatic brain injury. Epilepsy will be a long-term, serious consequence for many of these wounded warriors, resulting in difficult-to-control seizures, along with potential motor disability and cognitive decline. Traumatic brain injury also affects about 1.5 million American civilians annually. Dr. Pitkänen will investigate two pharmacological compounds that increase neuronal excitability as a way to assess if they can modify the neurobiological processes that lead to post-traumatic epilepsy (PTE). The ultimate goal is to develop treatments that could potentially prevent the development of PTE, as well as enhance motor and cognitive recovery, in an animal model of epilepsy.

David A. Prince, MD and Kevin Graber, MD Stanford University School of Medicine “Prevention of Epilepsy after Brain Injury” Because seizures after serious head injury often first occur weeks or even years later, there is a significant window of opportunity in which to intervene and potentially prevent the development of posttraumatic epilepsy (PTE). Building on past NIH- and CURE-funded studies, Drs. Prince and Graber will use three approaches in a rodent model to attempt to limit the excessive connections between nerve cells and the loss of inhibitory control of brain activity that contribute to epilepsy after injury. They will: 1) use gabapentin to limit the formation of new nerve connections in the brain; 2) use a substance (brain-derived neuronal growth factor) that nourishes and supports normal inhibitory nerve cells in order to protect them; and 3) manipulate a gene responsible for the development of excessive excitatory connections between nerve cells.

2009 Research Awards

Multidisciplinary Awards
One-year grants in support of collaborative research

The 2009 Madison Friends of CURE Award
This grant is jointly sponsored with matching funds from CURE.
	Steven Rothman, MD University of Minnesota Medical School, Minneapolis, MN Daniel Rode, PhD Washington University, St. Louis, MO “Optical Control of Focal Epilepsy with Caged Compounds” Focal seizures are often resistant to treatment with antiepileptic medications, and surgery to remove the affected area of the brain can cause permanent neurological deficits and may fail to control the seizures. Drs. Rothman and Rode will develop drugs that will be locally applied to the affected brain region that are only active when activated by a light (caged compounds). The goal of their research is to terminate seizures using compounds activated by light without affecting the function of the rest of the brain. If successful, this method could provide another mechanism for treating epilepsy without the side effects.

The 2009 UCB Award
This award is made possible through an unrestricted educational grant, and is jointly sponsored with matching funds from CURE.
	Audrey Yee, MD University of Colorado, Denver School of Medicine, Aurora, CO Amy Yee, PhD Tufts University, Boston, MA “Epilepsy and the Wnt Signaling Pathway” Epilepsy is initiated by an event such as a prolonged seizure and is sometimes followed with the development of spontaneous seizures, learning disabilities, and other neurological issues. Dr. Audrey Yee, an epilepsy researcher and clinical neurologist, and Dr. Amy Yee, a breast cancer and Wnt signaling researcher, will investigate new mechanisms and therapeutic strategies to treat epilepsy. The Wnt signaling pathway is abnormal in many cancers, but may also have an unexpected role in the initiation of epilepsy. They will explore whether Wnt signaling is activated in brain cells following a seizure and contributes to epilepsy.

The 2009 Axelrod Family Award
This grant is funded by the CJM Foundation.
	Lisa Bateman, MD University of California, Davis, CA Masud Seyal, MD, PhD University of California, Davis, CA “Efficacy of Fluoxetine in Reducing Ictal Hypoventilation in Patients with Partial Epilepsy” Disordered breathing occurs in one-third of seizures in people with uncontrolled partial epilepsy. Does disordered breathing play a role in Sudden Unexplained Death in Epilepsy (SUDEP)? It is not know, but we do know that serotonin (a brain chemical) plays a role in the control of breathing, and when researchers increase serotonin levels in an animal model of SUDEP, they were able to prevent respiratory failure. Dr. Bateman and her collaborators will investigate whether fluoxetine (commonly known as Prozac and which increases serotonin levels) improves respiratory function in individuals with intractable partial epilepsy.

The 2009 Rock the Block for Pediatric Epilepsy Award

Melanie Tallent, PhD Drexel University School of Medicine, Philadelphia, PA Gordon Lutz, PhD Drexel University School of Medicine, Philadelphia, PA “Directing Glutamate Receptor Alternative Splicing to Treat Epilepsy” Genes are the blueprint for making proteins in all of the cells in our bodies. The diversity of proteins is far greater than the number of genes, so a single gene can encode multiple proteins with distinct functions through a process called alternative splicing. The regulation of alternative splicing is disrupted in many neurological diseases, including epilepsy. Drs. Lutz and Tallent will focus on rescuing abnormal alternative splicing in the brain as an approach to reduce seizures and prevent epilepsy. They are hopeful that these studies will lead to a new understanding of the mechanisms of epilepsy and new approaches to therapy.

Jenny Hsieh, PhD The University of Texas Southwestern Medical Center Helen Scharfman, PhD The Nathan Kline Institute for Psychiatric Research “Postnatal Neurogenesis as a Therapeutic Target for Epilepsy” After birth, the brain continues to make new neurons. Research has shown that this process, called neurogenesis, is increased by seizures and by inducing epilepsy in an animal model of temporal lobe epilepsy (TLE). Several studies have provided evidence that these new neurons may contribute to recurrent seizures, while the results of other studies suggest that the new neurons are actually beneficial to the adult brain. Drs. Hsieh and Scharfman will collaborate to block neurogenesis in an animal model of TLE to resolve this issue. The results of this study will help determine if targeting neurogenesis is a potential therapy for the treatment of TLE.

Avtar Roopra, PhD Paul Rutecki, MD Corinne Burger, PhD University of Wisconsin, Madison “Assessing Metformin as an Anti-epileptogenic Drug” A third of individuals with epilepsy have seizures that cannot be controlled by available medications. Addressing this challenge requires an understanding of how nerve cells in the brain function and communicate with each other. Many individuals with epilepsy benefit from the use of the ketogenic diet, leading Drs. Roopra, Rutecki, and Burger to hypothesize that medications that control the body’s energy usage might also control epilepsy. They will collaborate to determine if the use of the common drug Metformin, which works by switching on a key sensor of energy levels in the brain—a protein called AMPK— can control epilepsy.

Quest Award
One-year grants for both established and early career investigators

The 2009 Griffin Leadbetter Award

Delia Talos, MD Children’s Hospital, Boston/Harvard Medical School, Boston, MA “Targeting the Chloride Transporter NKCC1 for Seizure Suppression in Tuberous Sclerosis Complex (TSC)” Epilepsy is a common and devastating occurrence for individuals with Tuberous Sclerosis Complex (TSC), and conventional antiepileptic drugs are often of limited benefit. Nerve cells affected by this genetic disease cannot react appropriately to certain inhibitory signals mediated by chemical neurotransmitters. Dr. Talos’ research will examine the altered nerve cell response in TSC, and determine if this alteration plays a crucial role in seizure development and the brain’s ability to respond to medication. Her study will investigate alterations of brain cell response to inhibitory signals in individuals with TSC, with the goal of identifying new therapeutic targets and developing more effective approaches to treat epilepsy.

SUDEP Awards
One-year grants for the study of Sudden Unexplained Death in Epilepsy (SUDEP)

The 2009 Christopher Donalty and Kyle Coggins Award

Alica M. Goldman, MD, PhD Baylor College of Medicine, Houston, TX “Submicroscropic Rearrangements in Cardiac Arrhythmia Genes: The Quest for Genetic Risk Factors for SUDEP” Dr. Goldman’s research is focused on identifying mutations in ion channel genes found in both the heart and the brain that underlie both cardiac arrhythmias and seizures, and may ultimately lead to Sudden Unexplained Death in Epilepsy (SUDEP). They have developed an ion channel gene specific microarray that will be used to analyze DNA samples from SUDEP cases and from individuals with intractable epilepsy. This research will be important in elucidating molecular risk factors underlying SUDEP. The long-term goal is to assist in defining an epilepsy population at risk for sudden death and allow initiation of life-saving preventative measures, as well as the design of gene specific therapies.

The 2009 Henry Lapham Memorial Award

Elizabeth Donner, MD University of Toronto, Hospital for Sick Children, Toronto, Canada “Registry of SUDEP in Children” Sudden Unexplained Death in Epilepsy (SUDEP) accounts for 34% of all sudden deaths in children. The objective of Dr. Donner’s research is to recognize which children are at the greatest risk of SUDEP. Using a network of collaborators across Canada, she will implement a registry that will collect data on every child in Canada with SUDEP. The registry will also be used to identify risk factors for SUDEP. Dr. Donner and her collaborators will develop recommendations for health care providers so they can recognize and identify those children at the greatest risk for SUDEP, as well as identify protective measures to prevent deaths.

Back to top

2008 Research Awards

Challenge Awards
One- to three-year grants for established investigators

* The 2008 Falk Medical Research Trust Award *
	Michael Wong, MD, PhD Washington University, St. Louis, MO “Stabilizing Dendritic Structure as a Novel Treatment for Epilepsy” Injury to the brain caused by repeated seizures may contribute to cognitive dysfunction and other neurological deficits in epilepsy patients. In this three-year project, Dr. Wong will investigate the direct effects of seizures on dendrites and dendritic spines, which are key components of synapses and potential sites of learning and memory in the brain. He will utilize modern cellular imaging techniques to visualize structural changes in dendrites in mice before and after seizures. The molecular mechanisms underlying these changes during seizures will be explored. Finally, drugs that can inhibit this dendritic injury will be tested, potentially leading to novel treatments for preventing seizure-induced brain injury.
* The 2008 Northwestern Dance Marathon Award *
	Steven L. Bealer, PhD University of Utah, Salt Lake City, UT “Predictors of Cardiac Risk and Beneficial Effects of Pharmacotherapy in Epilepsy” In patients with epilepsy, sudden cardiac death may occur following status epilepticus (prolonged seizures), in sudden unexplained death in epilepsy (SUDEP), and in patients with epilepsy and co-existing cardiac disease. However, the relationship between epilepsy, clinical indicators of cardiac risk, and the beneficial effects of drugs that protect the heart are not known. In this three-year project, Dr. Bealer will evaluate these relationships to determine which patients should be routinely evaluated for cardiac risk, and whether appropriate cardiac drug therapy reduces the risk of death.

Multidisciplinary Awards
One-year grants in support of collaborative research

* The 2008 Christopher Donalty and Kyle Coggins Memorial Award for Multidisciplinary Research *
	Dmytro Isaev, PhD Bogomoletz Institute of Physiology, Kiev, Ukraine Gregory L. Holmes, MD Dartmouth Medical School, Lebanon, NH “Reduction in Seizure Susceptibility through Modification of the Level of Extracellular Sialic Acid” Far too many individuals with epilepsy who take antiepileptic drugs continue to have seizures or suffer from serious medication side effects. Working together, Dr. Holmes (a pediatric neurologist) and Dr. Isaev (a senior researcher in general physiology of the nervous system) recently showed that they could dramatically reduce seizures by altering a naturally occurring compound in the brain called sialic acid. By reducing sialic acid, they have been able to turn down “the thermostat of the brain,” reducing brain excitability without causing any substantial side effects. In this one-year study, Drs. Holmes and Isaev will build upon these exciting preliminary results and determine whether modification of sialic acid reduces seizures in a mouse model of epilepsy and prevents the onset of epilepsy following brain injury.
	Gregory Mathews, MD, PhD Vanderbilt University Medical Center, Nashville, TN David Poulsen, PhD University of Montana, Missoula, MT “Targeted Enhancement of GABA Synthesis for Epilepsy Therapy” Despite a dramatic increase in new drugs available for epilepsy patients, more than 30% of patients still do not achieve seizure freedom. Therapies aimed at increasing GABA, the major neurotransmitter in the brain, are key targets for anticonvulsant therapies. However, traditional medications are heavily sedating with significant cognitive side effects. This one-year collaborative effort between Dr. Poulsen (a molecular virologist) and Dr. Mathews (a clinical epileptologist and basic neuroscientist) will explore the use of viral gene technology for enhancing GABA, offering the promise of new and less debilitating therapeutic options for epilepsy patients.

Quest Awards
One-year grants for both established and early career investigators

* The 2008 UCB Diamond Sponsorship Award *
	Christophe Bernard, PhD INSERM, Marseille, France “Dendritic HCN Channels as a Target against Epileptogenesis and for Improving Cognitive Deficits in Temporal Lobe Epilepsy” In addition to seizures, many patients with epilepsy struggle with memory and other cognitive deficits. Dr. Bernard has shown that temporal lobe epilepsy is associated with a loss of function of a specific protein in the brain called hyperpolarizing-activated cyclic nucleotide-gated ion channels (HCN). This loss not only makes the cell more excitable but also impairs cognitive function. In this study, Dr. Bernard’s goal is to determine whether the loss of HCN may actually cause epilepsy and/or cognitive dysfunction. By boosting HCN activity in animal models of epilepsy, using specific drugs or via genetic technology, this study may lead to new approaches to controlling seizures with the potential of also restoring cognitive function.
* The CURE 365 and Maggie Loeffel Award *
	Karin Borges, PhD Texas Tech University Health Sciences Center, Amarillo, TX “Anaplerosis: A Potential New Dietary Therapy for Epilepsy” Many patients with epilepsy do not respond to drugs or to the high-fat ketogenic diet. Triheptanoin, a tasteless and well-tolerated oil, is a component of the anaplerotic diet. This oil is believed to provide more energy to the brain, which may help to stabilize nerve cell activity and prevent seizures. In this one-year study, Dr. Borges will test, in mice, whether an anaplerotic diet can inhibit seizures. If so, this study could lay the groundwork for future investigation of this novel approach to treating epilepsy.

2008 Traumatic Brain Injury Awards

“Prevention of Epilepsy After Traumatic Brain Injury”
A Partnership with the United States Army Medical Research and Materiel Command (USAMRMC)

	David Prince, MD Kevin Graber, MD, co-investigator - Stanford University, Stanford, CA Prevention of Neocortical Post-traumatic Epileptogenesis There is often a delay between brain injury and development of seizures in lab animals and in humans. Dr. David Prince has shown that development of post-traumatic epilepsy in animals can be prevented by briefly treating the injured brain with a substance that blocks nerve cell messages. In this two-year study, they will use other approaches, such as the application of a drug that acts to decrease the action of an excitatory messenger normally pr esent. Other experiments will test whether increases in a gene that prevents both nerve injury and development of new connections will prevent post-traumatic epilepsy in animals. This grant is jointly sponsored by the USAMRMC and funds raised from the Northwestern University 2007 Dance Marathon.
	Detlev Boison, PhD Theresa Lusardi, PhD, co-investigator - RS Dow Neurobiology Lab, Legacy Research Portland, OR Prevention of Posttraumatic Epilepsy by Transient Modulation of Adenosine Receptors Adenosine is one of the brain’s own seizure-control substances and recent evidence suggests that epilepsy development is associated with a failure in the adenosine system. A frequent cause for the development of epilepsy is a previous traumatic brain injury. In this two-year study, Dr. Boison will examine how failures in the adenosine system develop as a consequence of brain injury, how these failures contribute to the development of spontaneous recurrent seizures, and how the development of epilepsy can be prevented by transient application of adenosine-related drugs during a critical window of time after the injury.
	Daniela Kaufer, PhD University of California, Berkeley, CA Alon Friedman, MD, PhD, co-investigator Ben-Gurion University of the Negev, Israel The Role of Serum Albumin and TGF-Beta in Post-Traumatic Epileptogenesis The mechanism by which traumatic brain injury leads to epilepsy is mostly unknown and, at present, no preventive treatment exists. Dr. Kaufer, along with co-investigator Dr. Alon Friedman of Ben-Gurion University of the Negev Beer-Sheva in Israel, discovered a novel mechanism that occurs following the injury-induced breakdown of the blood-brain barrier, leading to the development of epilepsy. This process is dependent on specific uptake of the serum protein albumin into the "supporting" cells of the brain, known as astrocytes. This two-year project aims to develop therapies that will prevent the generation of epilepsy following brain trauma.
	Jian Kang, MD, PhD - New York Medical College, New York, NY Roles of Glutamate-Induced Astrocytic Glutamate Release in Post-Traumatic Epilepsy Post-traumatic epilepsy is a common neurological disorder following brain injury. The cellular and molecular mechanism of this disease is still unknown. The goal of this two-year project is to study how glutamate release from astrocytes, the “supporting” cells of the brain, causes the development of post-traumatic epilepsy. In response to increased extracellular glutamate, astrocytes release a large amount of glutamate through fusion of a large vesicle. This may contribute to the cellular mechanism of post-traumatic epilepsy. This work may lead to a novel target for preventing post-traumatic epilepsy following brain injury.
	Adi Mizrahi, PhD - The Hebrew University of Jerusalem, Israel In Vivo Time-Lapse Imaging of an Epileptogenic Focus in Post-Traumatic Epilepsy In this three-year project, Dr. Mizrahi will study the changes within the brain that underlie the development of post-traumatic epilepsy in mice. He will use live imaging techniques in a mouse model of post-traumatic epilepsy to learn how brain cells react when post-traumatic epilepsy develops. These experiments will provide a direct view, at high resolution, of the actual dynamics of the development of epilepsy. Such in vivo experiments may lead to the discovery of new biological mechanisms that lead to epilepsy after brain injury.
	Philip Schwartzkroin, PhD - University of California, Davis, CA Dietary and Activity Treatments for Modulating Post-Traumatic Brain Hyperexcitability In this two-year project, Dr. Schwartzkroin will study potential protective therapies in a rat model of traumatic brain injury. He will examine the effects of a ketogenic diet administered both before and after the brain insult, including the potential addictive effects of the diet. In addition, because “enriched environment therapies” have been shown to promote the birth of new brain cells, Dr. Schwartzkroin will study the effects of exposure to such environments. If these simple and inexpensive treatments can reduce the expected brain cell damage associated with traumatic brain injury, and/or prevent the development of abnormal brain excitability, then these therapies could be applied to humans after traumatic brain injury (e.g., soldiers who have received head trauma in conflict).

Back to top

2007 Multidisciplinary Awards

	Anne Anderson, MD & Matteo Vatta, PhD - Baylor College of Medicine / Houston, TX 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.
	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.
	Scott Baraban, PhD & John Rubenstein, MD, PhD - University of California/ San Francisco, CA 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
	Julie Blendy, PhD, University of Pennsylvania, Philadelphia, PA & Brenda Porter, MD - Children’s Hospital of Philadelphia, Philadelphia, PA 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.
	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

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

2007 Quest Awards

	Nicholas Poolos, MD, PhD - University of Washington / Seattle, WA 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.
	Dwayne W. Godwin, PhD - Wake Forest University School of Medicine / Winston-Salem, NC 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.
	Janet Soul, MD, CM - Children’s Hospital Boston and Harvard Medical School/ Boston, MA 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.

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

2007 CURE Award Grantees

	Michael J. Kubek, PhD - Indiana University School of Medicine, Indianapolis, IN 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.
	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.
	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.
	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.
	H. Steve White, Ph.D. and Robert S. Fujinami, Ph.D. - University of Utah, Salt Lake City, UT 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.
	Jingqiong Kang, MD, PhD - Vanderbilt University Medical Center, Nashville, TN 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

	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.
	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.
	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.
	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.
	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.
	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.

Back to top

2006 CURE Award Recipients

	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.

Back to top

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.

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.

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.

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.

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.

Back to top

2004 Grant Recipients

Back to top

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

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