CURE Discovery: Spider Venom Peptide May Reduce Seizures

A new treatment for Dravet syndrome, a rare and catastrophic form of drug-resistant epilepsy, may soon be on the horizon thanks to the work of CURE grantees Dr. Glenn King of the University of Queensland and Dr. Steven Petrou of the Florey Institute of Neuroscience and Mental Health. Drs. King and Petrou identified a peptide found in spider venom which can reduce seizures and mortality in mice modeling the symptoms of human Dravet syndrome.1

The majority of Dravet syndrome cases are caused by mutations in a gene that lead to too little inhibition and too much excitation in the brain, triggering the hyperexcitability seen with seizures.2,3 Drs. King and Petrou found that the spider venom peptide works to restore the balance of inhibition and excitation in the brains of Dravet syndrome mice, decreasing hyperexcitability and reducing seizures. Furthermore, the team found that this peptide also decreases mortality in these mice.

Drs. King and Petrou next plan to investigate this peptide’s effects on other symptoms associated with Dravet syndrome, such as anxiety, autistic traits, and sleep disturbance. They will also explore ways to develop this peptide into a treatment for epilepsy, including methods of delivering the peptide into the brain.

Besides providing a potential new treatment for Dravet syndrome, these results are especially important because they highlight the therapeutic power of venomous substances, Dr. King notes. These substances work due to their ability to target the brain and alter its activity. Dr. King is optimistic that venomous substances may also be used in the treatment of types of epilepsy other than Dravet syndrome, as well as other brain disorders.

We at CURE are also hopeful this line of research will open new treatment possibilities for rare and difficult-to-treat epilepsies. As noted by Dr. King, the overall goal of this research is to develop therapeutics that will reverse all symptoms of Dravet syndrome and enable those with the disorder to live normal lives.

1 Richards et al. Selective Nav1.1 activation rescues Dravet syndrome mice from seizures and premature death. PNAS 2018; 115(34):E8077-E8085.
2 Bender et al. SCN1A mutations in Dravet syndrome: Impact of interneuron dysfunction on neural networks and cognitive outcome. Epilepsy Behav 2012; 23(3):177-186.
3 Liautard et al. Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome. Epilepsia 2013; 54(7):1251-1261.

Sudden Death Among Children with Epilepsy: 4x More Likely than Previously Thought

1.11 out of 1,000 children with epilepsy die suddenly each year, according to a Canadian study by CURE grantee Dr. Elizabeth Donner of the University of Toronto. (1) Dr. Donner’s estimates confirm 2017 results garnered from the Swedish National Death Registry that also found the annual rate of sudden death to be 1.11 per 1,000 children with epilepsy. (2)

Both of these recent studies are in contrast to previous estimates which showed that Sudden Death in Epilepsy (aka SUDEP) affects 1 in 4,500 children with epilepsy each year. (3)

Dr. Donner has spent much of her career identifying and studying cases of SUDEP to determine how often sudden death occurs in children with epilepsy and who is at risk. A recipient of CURE’s 2009 Sudden Unexpected Death in Epilepsy Award, Dr. Donner set out to create a Canadian pediatric SUDEP registry in collaboration with the Canadian Paediatric Surveillance Program, with the goal of obtaining data on every child with a sudden death and epilepsy.

Dr. Donner hopes that this increased understanding of how many children are affected by SUDEP will lead to the identification of risk factors. She aims to save lives by understanding which children with epilepsy are most at-risk, so that therapies can be developed to prevent sudden death.

Although there is currently no known ‘cure’ for SUDEP, the efforts of Dr. Donner and her team have increased understanding about this devastating consequence of epilepsy. Through the work of dedicated researchers like Dr. Donner, we may soon be able to not only identify those that are at risk for SUDEP but also offer ways to prevent SUDEP from occurring at all.

1 – Keller AE et al. Incidence of sudden unexpected death in epilepsy in children is similar to adults. Neurology 2018; 91(2):e107-e111.
2 – Sveinsson O et al. The incidence of SUDEP: A nationwide population-based cohort study. Neurology 2017; 89(2): 170-177.
3 – Harden C et al. Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2017; 88(17):1674-1680.

CURE Discovery: Transplanting Inhibitory Neurons Can Reduce Seizures

CURE Grantee Dr. Janice Naegele of Wesleyan University has been working on harnessing the brain’s own inhibitory power as a treatment to reduce excitability and “quiet” the overly excitable epileptic brain. As a promising first step, she and her team have successfully shown that transplantation of mouse inhibitory neurons into the mouse hippocampus – a brain structure that is often involved in epilepsy – can reduce the number of seizures in mice with temporal lobe epilepsy. (1)

Temporal lobe epilepsy is the most common form of epilepsy, with neuronal loss being one of its hallmark traits. (2,3) The loss of inhibitory neurons can be an important factor in the development or worsening of the disorder, (4) because the balance between excitatory and inhibitory neuronal activity is essential for proper brain function. Fewer inhibitory neurons can decrease inhibitory neurotransmission, in turn leading to excessive neuronal excitation, seizures, and epilepsy. One focus of Dr. Naegele’s epilepsy research has been to find a way to increase inhibition in the hyperexcitable epileptic brain. (5)

Dr. Naegele used her CURE grant to focus on transplanting both mouse and human inhibitory neurons into the hippocampus of mice with temporal lobe epilepsy. She hypothesized that these inhibitory neurons would wire up with existing neurons, increasing inhibitory transmission and decreasing the hyperexcitability that characterizes temporal lobe epilepsy. This type of treatment is called “regenerative medicine” because it uses healthy tissue to restore normal brain functioning. An advantage of regenerative medicine is that the transplanted cells can potentially replace lost or damaged inhibitory neurons and also integrate into the existing brain circuitry. This treatment would provide a cure for seizures by addressing the root cause, unlike standard antiepileptic drugs that simply treat the symptoms of seizures.

Indeed, as shown by advanced imaging techniques, the inhibitory neurons Dr. Naegele’s team transplanted into the brains of mice with temporal lobe epilepsy formed new, functional connections with excitatory neurons already present in the hippocampus, providing the increased inhibition that likely led to fewer seizures in these mice. (1)

Following the success of quieting seizures using the implantation of mouse inhibitory neurons, Dr. Naegele and her team are now focused on a means to quiet seizures by implanting human inhibitory neurons, pushing this research one step closer to being a viable treatment for people with epilepsy. As part of their strategy, they are keeping in mind important potential differences in neuronal generation and transmission between humans and mice. (6)

Dr. Naegele’s research brings an exciting possibility to the future of epilepsy treatment: the transplantation of a type of neuron that already exists in the human brain with the goal of stopping seizures. While work still remains, CURE applauds the progress Dr. Naegele has made thus far. We share Dr. Naegele’s hopes that her approach becomes a non-drug method of treating those affected by not only temporal lobe epilepsy, but other forms of epilepsy as well.

1 Henderson et al. Long-term seizure suppression and optogenetic analysis of synaptic connectivity in epileptic mice with hippocampal grafts of GABAergic interneurons. J Neurosci 2014; 34(40):13492-13504.
2 Pitkänen A, Sutula TP. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Neurol 2002; 1(3):173-181.
3 Engel J Jr, Williamson PD, Weiser HG. Mesial temporal lobe epilepsy. In: Epilepsy: a comprehensive textbook (Engel J Jr, Pedley TA, eds) 1997: 2417-2426.
4 Kumar SS, Buckmaster PS. Hyperexcitability, interneurons, and loss of GABAergic synapses in entorhinal cortex in a model of temporal lobe epilepsy. J Neurosci 2006; 26(17):4613-4623.
5 Van Zandt MA, Naegele JR. GABAergic synapse dysfunction and repair in temporal lobe epilepsy. (2017) Synaptic Plasticity Thomas Heinbockel, IntechOpen; DOI: 10.5772/67218. Available from: https://www.intechopen.com/books/synaptic-plasticity/gabaergic-synapse-d….
6 Naegele JR. Controversial brain study has scientists rethinking neuron research. (2018) Available from: https://theconversation.com/controversial-brain-study-has-scientists-ret…

CURE Discovery: New Cause of Severe Childhood Epilepsy Found – Genetic Mutation in the CUX2 Gene

CURE Grantee Dr. Gemma Carvill has identified a new cause of epilepsy: a mutation in the gene CUX2. Dr. Carvill’s discovery was recently published in the Annals of Neurology.1

The discovery provides an important advance in our understanding of the causes of a class of severe childhood epilepsies. This class includes childhood epileptic encephalopathy, an aggressive and severe group of treatment-resistant epilepsy disorders in which children can have profound cognitive and neurological deficits.2,3

Dr. Carvill began her research into the ways specific genetic mutations lead to childhood epileptic encephalopathy in 2015 as the result of a 1-year CURE Taking Flight Award. This award program encourages young investigators to conduct independent research which could lead to a cure for epilepsy. When Dr. Carvill recieved the CURE Taking Flight Award, she was a Postdoctoral Fellow at the University of Washington.

Dr. Carvill studied the ways genetic mutations lead to epilepsy. Her initial findings suggested that mutations in a class of genes important in determining the structure of DNA could impact several genes involved in epilepsy, making this class of genes a potential target of future epilepsy therapy development.

Since receiving her CURE award, Dr. Carvill’s career has certainly “taken flight” – she is now Assistant Professor of Neurology and Pharmacology at Northwestern University. Still, Dr. Carvill has remained committed to her quest to understand the genetic mechanisms behind severe childhood epilepsy. In her latest study, Dr. Carvill partnered with Dr. Gaetan Lesca of the Lyon University Hospital, located in France, to identify de novo mutations in the gene CUX2 as a new cause of epilepsy. De novo mutations are changes present only in the affected patient and not in their healthy parents. CUX2 is important in binding DNA and promoting the expression of certain target genes. Mutations in CUX2 cause errors in this process that can lead to epilepsy.

Dr. Carvill’s report details her international study of 9 patients aged 6 months to 21 years who first began having seizures early in life. To identify the mutation in the CUX2 gene, Dr. Carvill and her team used, among other techniques, a test called whole exome sequencing. This test analyzes a person’s genes to identify changes in their DNA. All 9 patients had the same CUX2 mutation. The team found that the majority of these patients had severe treatment-resistant epilepsy that started early in life, severe intellectual disability, and did not have speech appropriate for their age.

Besides finding an important genetic cause of severe childhood epilepsy, which can now be targeted for the development of therapeutic interventions, Dr. Carvill’s collaboration with Dr. Lesca highlights the importance of international efforts to identify new genes important in epilepsy. As Dr. Carvill notes, these genetic mutations are very rare and therefore collaborative efforts with multiple patient populations make it more likely that a rare genetic mutation can be identified and studied.

In the future, Dr. Carvill plans to further explore the genetic mechanisms behind these devastating childhood epilepsies. Her goal, which we at CURE share, is that treatments and cures can be found for all of the amazing children affected by epilepsy and their wonderful families, too.

Citations

1 Chatron N et al. The epilepsy phenotypic spectrum associated with recurrent CUX2 variant. Ann Neurol2018; 6 [Epub ahead of print]
2 Cross H and Guerrini R. The epileptic encephalopathies. Handb Clin Neurol 2013; 111:619-626.
3 Jehi L, Wylie E, Devinsky O. Epileptic encephalopathies: Optimizing seizure control and developmental outcome. Epilepsia 2015; 56(10):1486-1489.

CURE Discovery: Potential Target Area in the Brain for Prevention of Epilepsy-Related Sudden Death

An area of the brain known as the amygdala may be critical in the conscious control of breathing, making it an important target area for research into epilepsy-related sudden death, according to a study recently published by CURE Grantee Dr. William Nobis of Northwestern University Feinberg School of Medicine.1 As part of a team led by Dr. Christina Zelano, also of Northwestern University, Dr. Nobis found that stimulation of the amygdala consistently induced apnea, or disrupted breathing, in a group of individuals with temporal lobe epilepsy. This finding is significant because it points to a possible role of the amygdala in what may be the most severe epilepsy-related complication, Sudden Unexpected Death in Epilepsy (SUDEP).

SUDEP occurs when a seemingly healthy person with epilepsy dies for no obvious reason,2 most often at night or during sleep. While research suggests that several factors including respiratory and cardiac dysfunction contribute to SUDEP,3,4 the precise biological processes remain unknown. By implanting electrodes into the brains of seven patients undergoing surgical evaluation for temporal lobe epilepsy, Dr. Nobis and his team were able to pinpoint specific regions of the amygdala that are important in controlling respiration, identifying areas possibly important in the cessation of respiration that characterizes SUDEP. Furthermore, the team found that by instructing patients to inhale during an apnea-inducing stimulation of the amygdala, they were able to prevent apnea providing an area upon which to focus development of therapeutic strategies to prevent SUDEP.

With funding from CURE, Dr. Nobis is now pushing this research to uncover the mechanisms behind SUDEP even further. He and his team think that the amygdala may be activated during seizures, causing it to lead to cessation of respiration and SUDEP. By using a genetic animal model of epilepsy that has a high rate of SUDEP, the team hopes to identify and examine the specific neurons within the amygdala that project to important respiratory centers in other parts of the brain, allowing the amygdala to influence respiratory function – and the loss of respiratory function that occurs in SUDEP.

Early results from Dr. Nobis’s current CURE project have begun to identify populations of neurons in the amygdala that project to areas of the brain important in respiration. The team next plans on examining how these neurons are activated in response to seizures, and how changes in the excitability of these neurons might correspond with changes in respiratory function that could lead to SUDEP.

In the future, Dr. Nobis hopes to be able to determine whether it is possible to target this subset of neurons within the amygdala to prevent SUDEP from occurring, providing a large step forward for SUDEP research and possible therapies for SUDEP prevention. Thanks to CURE-funded researchers like Dr. Nobis, we are moving closer to being able to eliminate the sudden and devastating death of individuals with epilepsy.

1 Nobis WP et al. Amygdala-stimulation-induced apnea is attention and nasal-breathing dependent. Ann Neurol 2018; 83(3):460-471.
2 Nashef. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 1997; 38(11 Suppl):S6-8.
3 Surges et al. Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms. Nat Rev Neurol 2009; 5(9):492-504.
4 Bagnall et al. Genetic basis of sudden unexpected death in epilepsy. Front Neurol 2017; 8:348.

CURE Discovery: Genetic Research Finds Potential Alternatives to Brain Surgery for Children with Cortical Dysplasia

A Potential Alternative is Already in Clinical Trial

Recent research by CURE grantee Dr. Jeong Ho Lee of the Korea Advanced Institute of Science and Technology has shed important light on the genetic mutations that lead to focal cortical dysplasia, a severe form of pediatric epilepsy that inadequately responds to available treatment options. Genetic mutations were found in the brain tissue of individuals affected by a particular subtype of focal cortical dysplasia (focal cortical dysplasia type II) that is characterized by brain abnormalities, leading to seizures and epilepsy.

Conventional genetic testing methods to identify genetic mutations in those with epilepsy often use blood or saliva from patients. However, these latest results from Dr. Lee and his team suggest that certain epilepsy-related gene mutations may only be detectable when brain tissue is analyzed.

Brain-Only Mutations in Genes that Cause Focal Cortical Dysplasia

By comparing blood and saliva samples to samples of brain tissue from a group of 40 individuals who had previously undergone brain surgery for focal cortical dysplasia type II, Dr. Lee and his team found that a significant number of these individuals (12.5%) had brain-only mutations in genes TSC1 and TSC2. Together with the previous pioneering work of his team to identify brain-only mutations in the MTOR gene in individuals with focal cortical dysplasia type II, they revealed that brain-only mutations in genes within the mTOR brain signaling pathway (including the genes TSC1, TSC2 and MTOR) are found in up to 30% of individuals with focal cortical dysplasia. The fact that these mutations were found only in the brain means that these mutations would be undetectable by conventional genetic testing methods, suggesting that investigation of brain-only mutations should be explored to a greater extent.

In addition to identifying brain-only mutations leading to focal cortical dysplasia, Dr. Lee and his team also addressed the current lack of adequate animal models to better study the disorder. The team was able to successfully recreate the brain-only mutations in genes TSC1 and TSC2 in developing mice, providing a much-needed animal model for further examination of the ways in which gene mutations can lead to focal cortical dysplasia type II.

Clinical Trials for the Treatment of Focal Cortical Dysplasia

Furthermore, the team provided evidence that mTOR inhibitors, such as rapamycin or everolimus, are promising anti-epileptic drugs for the treatment of focal cortical dysplasia. In fact, everolimus is currently under phase II clinical trial for the treatment of focal cortical dysplasia.

As noted by Dr. Lee, because focal cortical dysplasia is a drug-resistant epilepsy, many children with the disorder require invasive brain surgery as treatment. However, even in cases where surgery is performed, up to 40% of these children may still have seizures. By identifying genes associated with focal cortical dysplasia as well as creating a new way of studying the genetic mechanisms behind the disorder, Dr. Lee and his team have made progress towards the creation of novel, non-surgical targets at which to aim treatments for this devastating form of drug-resistant childhood epilepsy.

[1] Lim et al. Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am J Human Genet 2017; 100(3):454-472.
[2] Guerrini et al. Diagnostic methods and treatment options for focal cortical dysplasia. Epilepsia 2015; 56(11):1669-86.
[3] Gaitanis and Donahue. Focal cortical dysplasia. Ped Neurol 2013; 49:79-87.
[4] Poduri et al. Genetic testing in the epilepsies – developments and dilemmas. Nat Rev Neurol 2014; 10(5):293-299.
[5] Lim et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 2015; 21(4):395-400.

CURE Discovery: Preventing Post-Traumatic Epilepsy with 2-Deoxy-D-Glucose Treatment

The latest results from a CURE-funded grant represent a promising advance in the quest to prevent post-traumatic epilepsy. Dr. Thomas Sutula from the University of Wisconsin and his team have found that the administration of 2-Deoxy-D-Glucose (2DG) following a traumatic brain injury can significantly reduce the subsequent development of post-traumatic epilepsy in a rodent model.

The finding that 2DG can prevent the development of post-traumatic epilepsy in rats is exciting for several reasons. 2DG is a sugar-like molecule that has been proposed to mimic the ketogenic diet – a diet that is highly effective in the treatment of difficult-to-treat epilepsies. Therefore, like the ketogenic diet, 2DG may also have therapeutic effects for individuals that have already developed epilepsy (in this case, post-traumatic epilepsy). 2DG is also already being used in the treatment of other illnesses, including cancer, and can likely progress rapidly to a clinical trial for post-traumatic epilepsy. Furthermore, with this research, Dr. Sutula and his team have successfully utilized a novel rat model that more readily develops a post traumatic-epilepsy-like syndrome with frequent seizures following traumatic brain injury, providing a great research tool in the quest for treatments and a cure for post-traumatic epilepsy.

Post-traumatic epilepsy is a type of epilepsy that develops following a traumatic brain injury such as a bump or blow to the head. Post-traumatic epilepsy accounts for nearly 20% of all symptomatic epilepsies in the general population, and is one of the most common causes of acquired epilepsy. Post-traumatic epilepsy can be particularly devastating because no known prevention or cure for the disorder currently exists.

Because post-traumatic epilepsy can develop months or even years after an initial traumatic brain injury, there is a critical window of time during which the development of post-traumatic epilepsy might be prevented, if only a preventative measure were in existence. For these reasons, Dr. Sutula’s finding that 2DG significantly reduces the development of post-traumatic epilepsy in his novel breed of rat within this critical window is an important one.

In the future, Dr. Sutula and his team plan on taking strategic steps to push their research forward towards an Investigational New Drug trial to test the effectiveness of this drug in the prevention of post-traumatic epilepsy in humans. In this way, Dr. Sutula hopes that his research will impact the lives of individuals suffering from post-traumatic epilepsy, or those with the potential to develop post-traumatic epilepsy, as soon as possible.

Stopping Acquired Epilepsy Before It Starts? CURE Researcher Identifies a Possible Epilepsy Biomarker

Annamaria Vezzani, PhD, and her team have identified the protein high-mobility group box 1 (HMGB1) as a potential biomarker for epilepsy and have uncovered a potential new treatment for the disease, using a rat model of brain injury and epilepsy. This promising work addresses one of the most important focus areas in modern-day epilepsy research—the search for a biomarker, or some substance that doctors can measure that would provide an indication that a person is likely to develop epilepsy.1

Dr. Vezzani of the Mario Negri Institute for Pharmacological Research in Milan, Italy and her team found that HMGB1 levels were increased in both the brain and blood in the period before the rats developed epilepsy and this increase was maintained during disease development2,3—an indication that HMGB1 levels might be measured as a sign of impending epilepsy. They then found that a combination of drugs already used in medical practice prevents both the increase in HMGB1 levels and, perhaps most excitingly, delayed the onset of epilepsy, blocked the progression of the disease and eliminated impairments in memory.3

HMGB1 is normally released in the brain during the process of neuroinflammation, the brain’s response to injuries, trauma or infections such as those that might lead to epilepsy.2,4 Although HMGB1 signals the brain to repair damaged tissue, too much HMGB1 can cause damage, and neuroinflammation has been associated with epilepsy.2,3,5 The finding that HMBG1 release is increased in the brain during the period in which epilepsy develops and is measurable in blood may allow HMGB1 to serve as a biomarker for epilepsy: doctors could measure blood levels of HMGB1 to determine which individuals are more likely to develop the disorder. Targeting the neuroinflammation that leads to increased HMGB1 with drugs already in clinical use could also create a new therapeutic area to prevent epilepsy from developing or improve its clinical course.

This impactful work by CURE researcher Dr. Vezzani and her team carries with it the possibility of critically affecting the diagnosis and prognosis of patients that are at risk of developing epilepsy. By using increased blood levels of HMGB1 as a biomarker for epilepsy and subsequently lowering these levels with drugs already being used clinically, doctors may soon be able to stop the disorder in its tracks.

“We are excited about the identification of HMBG1 as a potential biomarker that could predict onset of epilepsy,” states Laura Lubbers, PhD, Chief Scientific Officer at Citizens United for Research in Epilepsy (CURE). “Now, this important finding needs to be confirmed in people who have experienced a brain injury and are at risk for developing epilepsy.”

“With this research, Dr. Vezzani and her team have provided hope that a treatment for preventing acquired epilepsy before it occurs is on the horizon,” says CURE CEO Kate Carr. “We thank both Dr. Vezzani as well as our supporters who have made such research possible through their generous donations.”

1 Pitkänen et al. Advances in the development of biomarkers for epilepsy. Lancet Neurol 2016; 15(8):843-856.
2 Walker et al. Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy. J Clin Invest 2017; 127(6):2118-2132.
3 Terrone et al. Preventing epileptogenesis: A realistic goal? Pharmacol Res 2016; 110:96-100.
4 Vezzani et al. Infections, inflammation and epilepsy. Acta Neuropathol 2016; 131(2):211-234
5 Pauletti et al. Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain 2017; 140(7):1885-1899.