Epilepsy Research Findings: March 2020

This month’s research highlights feature promising work by former CURE Grantees and CURE partners.

Former CURE Grantee Dr. Kristina Simeone’s recent research has uncovered a potential predictive biomarker for Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Simeone’s work was supported by the Benninghoven family in memory of Cameron Benninghoven.

We also feature research by another former CURE Grantee, Dr. Angelique Bordey, who along with her research team published exciting findings showing that targeting a particular protein in the brain can reduce or prevent seizures in mouse models of difficult-to-treat epilepsy.

We are also highlighting research by Dr. Daniel Correa and his work through the EpiBioS4Rx Public Engagement Core, a project in which CURE participates. Dr. Correa’s research indicates that greater efforts should be made to ensure online epilepsy health education materials are more easily understandable to the general population to increase epilepsy literacy.

These findings, as well as others, can be found below:

Research Discoveries & News

  • SUDEP: Research featuring the work of former CURE Grantee Dr. Kristina Simeone found a potential time-based biomarker of impending SUDEP. Dr. Simeone found cardiac and respiratory dysfunction that changed over time in mice at risk for SUDEP and may serve as a biomarker to indicate who is at risk for SUDEP. She also found that this dysfunction could be lessened by blocking a particular type of receptor in the brain, the orexin receptorLearn More

    This research was supported by the Benninghoven family in memory of Cameron Benninghoven.

  • Uncontrolled Epilepsy Treatment: Former CURE Grantee Dr. Angelique Bordey and her research team utilized an experimental drug to reduce seizures in mouse models of tuberous sclerosis complex (a rare genetic epilepsy) and a subset of focal cortical dysplasia type II (a brain malformation causing epilepsy). The team found that seizures can be prevented or reduced by targeting a protein called actin-cross linking protein filament A which is often elevated in the brains of humans with these epilepsies. Learn More
  • Online Epilepsy Education: Researcher Dr. Daniel Correa found that the majority of online health education materials related to traumatic brain injury (TBI), epilepsy, and post-traumatic epilepsy (PTE) do not meet the sixth-grade reading level recommendation from most health organizations. This study was published as part of the CURE-supported EpiBioS4Rx Public Engagement Core, an NINDS initiative focused on ensuring successful future clinical trials to prevent the development of PTE following TBI. This study suggests that improving the readability of health education materials may increase epilepsy-related health literacy, leading to more effective recruitment efforts for future clinical trials, as well as better patient-centered results. Learn More
  • New Treatment: Valtoco (diazepam), a nasal spray intended to treat seizure emergencies in patients 6 years of age and older, is now commercially available in the US. Learn More
  • Clinical Trial: Engage Therapeutics announced that its Phase 2b StATES study of Staccato® alprazolam, an orally inhaled therapy designed to terminate an active epileptic seizure, met its primary endpoint. This endpoint was a proportion of responders achieving cessation of seizure activity within two minutes of treatment administration and no recurrence within two hours. Learn More
  • Post-Traumatic Epilepsy: Research suggests that rats treated with certain drugs within a few days of a traumatic brain injury have a dramatically reduced risk of developing epilepsy later in life. Researchers found that suppressing an immune system receptor called Toll-like receptor 4 shortly after brain injury reduces seizure susceptibility and neuronal excitability in an important part of the brain called the hippocampus. Learn More
  • SCN8A Encephalopathy: A therapy that enables researchers to control gene expression in the brain, called antisense oligonucleotides (ASOs), has been utilized to stop seizures in a mouse model of SCN8A encephalopathy, a rare childhood epilepsy. By using ASOs, researchers delayed seizure activity and increased the lifespan of these mice. Learn More

The CURE Epilepsy Research Mobile App delivers research news to the palm of your hand! With frequent updates, you’ll always be in-the-know about the latest in epilepsy science. Download today. iOS | Android

Drug Shows Promise in Reducing Seizures in Those with Severe Epilepsy

Featuring the work of former CURE Grantee, Dr. Angelique Bordey

People who suffer severe and recurring seizures have few good treatment options, but an experimental drug can reduce seizures in mouse models of two underlying disorders that can cause chronic epilepsy, Yale researchers report in the journal Science Translational Medicine.

Severe forms of epilepsy caused by brain lesions or malformations are usually treated with surgeries and anti-seizure medication. However, the prognosis for many of these patients remains poor, said Angelique Bordey, professor of neurosurgery and of cellular and molecular physiology.

“This is a completely new treatment with unexpected benefits,” Bordey said.

In a study led by first author Longbo Zhang, the Bordey lab reports the elevated expression of actin-cross linking protein filamin A (FLNA) in the brain tissue of many patients with two genetic disorders linked to intractable seizures: tuberous sclerosis complex (TSC) and a subset of focal cortical dysplasia type II. Both disorders are associated with disruption of a regulator of cell growth and cortical malformations with enlarged, dysmorphic cells that are responsible for seizures. Using a drug targeting FLNA to treat mice models of the disorders, Bordey’s lab found that cell enlargement and seizures could be prevented or reduced.

Bordey said her lab plans to explore whether the drug will be effective in treating people with epilepsy and perhaps other symptoms of TSC, such as behavioral problems, including social and intellectual deficits.

The work was primarily funded by the National Institute of Neurological Disorders and Stroke.

Mom and businesswoman working with laptop computer at home and playing with her baby girl. Horizontal shape, front view, waist up

Marinus Pharmaceuticals Completes Targeted Enrollment in Pivotal Phase 3 Study for CDKL5 Deficiency Disorder

Marinus Pharmaceuticals, Inc., announced it has reached the 100 patient enrollment target for the Marigold Study.  The Marigold Study is a pivotal Phase 3 study evaluating oral ganaxolone in children and young adults with CDKL5 Deficiency Disorder (CDD), a rare refractory form of pediatric epilepsy with no currently approved treatments.  The Company will continue enrollment through the end of the month to capture the remaining few patients in the screening phase.

“Enrolling 100 patients in our registrational, pivotal Phase 3 trial evaluating ganaxolone in children with CDD is a significant milestone for both Marinus and the CDD community,” said Joe Hulihan, M.D., Chief Medical Officer of Marinus. “Our ability to identify and rapidly enroll qualified patients into this study is indicative of the significant need for a new therapy to reduce seizure burden and improve patient outcomes. The study has been well conducted and we are encouraged by the limited adverse events, low dropout rates and the vast majority of patients entering the open-label extension. We are appreciative of the patients and broader CDD community for their participation in the Marigold study and we remain committed to addressing the unmet need of these patients who currently have no approved treatment options.”

New Therapy Stops Seizures in Mouse Model of Rare Childhood Epilepsy

SCN8A encephalopathy could be improved with a treatment already approved for other uses.

Seizure disorders in babies are frightening and heartbreaking. A new basic science breakthrough offers hope for a potential treatment for rare developmental and epileptic encephalopathies resulting from a single genetic mutation. The gene in question, called SCN8A, controls a sodium channel that allows neurons to transmit an electric signal.  When this gene is mutated, these channels can become hyperactive, resulting in recurrent seizures. The average age of onset of SCN8A-related encephalopathy is just four months old.

“Approximately half of patients are severely impaired and cannot walk or talk,” says Miriam Meisler, Ph.D. Meisler is the Myron Levine Distinguished University Professor of Human Genetics and a Professor of Neurology at U-M Medical School. She and her team have studied this disease and its genetic mechanisms for many years, painstakingly developing mouse models that would allow for testing new therapies.

Within the past few years, a new therapy called antisense oligonucleotide (ASOs) has entered the scene, enabling researchers to control gene expression. ASOs are short DNA or RNA molecules designed to block messenger RNA molecules and their encoded proteins. This allows them to control the amount of RNA expressed by mutated genes, dampening their effects on the body.

The team realized the potential of ASOs for this seizure disorder. Their first achievement was developing a mouse model that accurately and predictably mimicked the disease in people. They generated a mouse with the same SCN8A mutation found in several patients but with the mutation turned off long enough to test the therapy.

Developing mice with an “on switch”, they were able to administer the ASO, and then turn on the mutation. “The effect was dramatic and unambiguous,” says Meisler. “We had a four-fold increase in lifespan, with added effects of repeated treatments.” There was no evidence of low-level seizure activity in the treated mice.

Epilepsy Research Findings: February 2020

Among the articles featured this month, we highlight the work of former CURE Grantee Dr. Annapurna Poduri, whose recent study argues for early use of whole exome sequencing and repeated analysis to identify the genetic cause of epilepsy in children. Dr. Poduri’s study supports the idea that reanalysis can aid in diagnosis. We also highlight Dr. Tristan Shuman, whose CURE-funded work sheds light on how epilepsy can affect cognition.

You can find more detail about our CURE Grantees’ work, as well as additional intriguing studies, below.

Research Discoveries & News

  • Epilepsy Genetics: In a study featuring the work of past CURE Grantee Dr. Annapurna Poduri, authors argue that use of whole exome sequencing with reanalysis of genetic data can, in some cases, more quickly lead to the identification of genetic variants associated with epilepsy in patients. Learn More
  • Epilepsy and Cognition: A study partially funded by CURE investigated the ways epilepsy affects navigation in mice. CURE Grantee Dr. Tristan Shuman and collaborators report that a particular feature of epilepsy – namely the “desynchronization” of neurons in the brain that are important in cognition – causes deficits in spatial information coding. Learn More
  • Dravet Syndrome: Researchers report that treating a mouse modeling Dravet syndrome with a small molecule reduces abnormal brain activity and improves cognitive function. The study states that the molecule enhances the function of a particular type of brain receptor found at the connection points between neurons. Learn More
  • Epilepsy and Technology: Smartphone videos taken by witnesses could help physicians diagnose seizures. Researchers concluded that patient-generated smartphone videos can help predict inpatient video-EEG diagnosis of epilepsy and add valuable information to the patient’s history and physical examination. Learn More
  • Angelman Syndrome: Using human nerve cells and three-dimensional “mini brains,” researchers have found that dysfunctional potassium channels may underlie the development of seizures associated with Angelman syndrome. Learn More
  • Epilepsy Benchmarks: These articles review the NINDS Epilepsy Benchmarks, examining progress made in epilepsy research and identifying priorities for the next phases of research. This is a process that continues to evolve to reflect scientific advances and community research priorities over time. Learn More
    • The Benchmarks: Progress and Emerging Priorities in Epilepsy Research – Learn More
    • Epilepsy Benchmarks Area I: Understanding the Causes of Epilepsies and Epilepsy-Related Neurologic, Psychiatric and Somatic Conditions – Learn More
    • Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression – Learn More
    • Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions without Side Effects – Learn More
    • Epilepsy Benchmarks Area IV: Limit or Prevent Adverse Consequences of Seizures and Their Treatment Across the Life Span – Learn More

The CURE Epilepsy Research Mobile App delivers research news to the palm of your hand! With frequent updates, you’ll always be in-the-know about the latest in epilepsy science. Download today. iOS | Android

Early Research Identifies Ion Channels as Key Players and Potential Therapeutic Target in Angelman Syndrome Epilepsy

Using human nerve cells and three-dimensional “mini brains,” researchers have found that dysfunctional potassium channels may underlay the development of seizures associated with Angelman syndrome.

Their study, “Potassium channel dysfunction in human neuronal models of Angelman syndrome,” was published in the journal Science.

Angelman syndrome (AS) is a complex genetic disorder that primarily affects the nervous system, and is characterized by developmental delay, learning disabilities, speech difficulties, and physical incapacity. Seizures are also a common symptom, affecting around 90% of patients.

The disease is caused by genetic defects in the UBE3A gene, which compromises the production of an enzyme called ubiquitin protein ligase E3A in certain areas of the brain. This enzyme flags other proteins to be degraded, as part of the natural cellular process for removing damaged or unnecessary proteins.

UBE3A plays a critical role in the development and function of the nervous system, helping to balance protein levels at the synapse — the junction between two nerve cells that allows them to communicate.

The team found that specific ion channels, called large conductance calcium- and voltage-activated big potassium (BK) channels — which allow potassium to pass through cells — were dysregulated in AS neurons. This seemed to be one of the reasons why AS patients frequently experience seizures.

In normal neurons, the UBE3A enzyme targets these ion channels for degradation, but in neurons from AS patients, the absence of a functional enzyme leads to the accumulation of an excessive number of potassium channels.

Too many of these channels leads to the hyperactivity of brain networks which, in turn, results in epileptic seizures.

When researchers treated neurons with agents that specifically block these potassium channels, normal brain network activity was restored in both human and mouse neurons. Importantly, upon treatment, seizure severity was reduced in an AS mouse model.

Novel Model Predicts Drug-Resistant Epilepsy in Children With Cerebral Palsy

A low Apgar score at 5 minutes, neonatal seizures, focal-onset epilepsy, and focal slowing on electroencephalogram (EEG) are risk factor variables that cumulatively form an accurate model for predicting the risk for drug-resistant epilepsy in children with cerebral palsy. This is according to results of a study in the Journal of Child Neurology.

The study was a single-center, observational, retrospective chart review of 118 children with cerebral palsy and either drug-resistant epilepsy (n = 52) or controlled epilepsy (n = 66). Several clinical variables and patient characteristics were analyzed regarding their association and the incidence of drug-resistant epilepsy.

According to the investigators, this study may assist healthcare practitioners to “complete a clinical picture of ‘high-risk epilepsy’ and thereby further assist in the consideration of alternative therapeutic avenues in reaching the goal of reducing the burden of poor seizure control in children with cerebral palsy.”

Ways to Give

Physically Active Children with Epilepsy Have Good Objective Sleep Duration and Efficiency Despite Subjective Reports of Fatigue and Sleep Problems

OBJECTIVE: The aim of this study was to longitudinally characterize in children with epilepsy the objective and subjective sleep quality and the relationship between increased physical activity and sleep as well as measures of psychosocial well-being.

METHODS: Baseline physical activity and sleep were established in children with epilepsy over four weeks, prior to a 12-week exercise intervention (weekly meeting with exercise counselor). Participants continuously wore a wrist pedometer (Fitbit Flex®) to capture daily number of steps, sleep efficiency, and total sleep time. The Early Childhood Epilepsy Severity Scale (E-Chess) assessed baseline epilepsy severity. Subjective sleep quality (Children’s Sleep Habits Questionnaire, CSHQ), quality of life (KIDSCREEN-27; Pediatric Quality of Life Inventory, PedsQL™, 4.0 Core), fatigue (PedsQL™ Multidimensional Fatigue Scale), depression (Children’s Depression Inventory-Short), and anxiety (Multidimensional Anxiety Scale for Children) were assessed pre- and post-interventions.

RESULTS: Our cohort of 22 children with epilepsy aged 8-14 years was similarly active to peers (11,271 ± 3189 mean steps per day) and displayed normal sleeping patterns (mean sleep efficiency: 87.4% ± 3.08 and mean total sleep time: 521 ± 30.4). Epilepsy severity assessed by E-Chess was low to moderate (median baseline E-Chess score of 6, interquartile range: 5-7). Study outcomes did not change with the intervention. Older children and those with lower baseline activity were more likely to increase their activity during the intervention. Changes in physical activity were not associated with changes in sleep outcomes when accounting for age, sex, and baseline E-Chess score. Subjective sleep quality marginally improved with the intervention (CSHQ total score: 44.5 ± 5.8 at baseline and 41.6 ± 7.2 at the end of study, p = 0.05). Quality of life, fatigue, depression, and anxiety did not change with the intervention (p = 0.55, 0.60, 0.12, and 0.69, respectively).

SIGNIFICANCE: Children with epilepsy who are as active as peers without epilepsy have good objective measures of sleep despite self-reported fatigue and parent-reported sleep problems. The physical activity of initially less active and older children with epilepsy may benefit from an exercise counseling intervention.

Gladstone researchers Jorge Palop and Keran Ma are collaborating with Jesse Hanson from Genentech to develop therapies for Alzheimer's disease and Dravet syndrome.

New Small Molecule to Treat Alzheimer’s Disease and Dravet Syndrome

Gladstone researchers, in collaboration with Genentech, a member of the Roche group, have shown therapeutic efficacy of a new experimental drug in mouse models of Alzheimer’s disease and a rare genetic form of epilepsy known as Dravet syndrome. The small molecule increases the activity of a subset of neurotransmitter (NMDA) receptors that are found at synapses, the connection points between neurons. These receptors are known to support cognition and memory by enhancing communication between neurons. The new research shows that enhancing the activity of synaptic NMDA receptors helps restore the brain’s rhythms to normal patterns, and improves memory.

“Before now, we haven’t had ideal tools to enhance synaptic NMDA receptors,” said Gladstone Associate Investigator Jorge Palop, Ph.D., senior author of the study, which was published in the journal Cell Reports. “Now, the ability to specifically target these receptors opens up a lot of new possibilities for treating cognitive disorders.”

“This is the first time we’ve explored what this type of experimental drug does in animal models,” said Jesse Hanson, a scientist at Genentech and lead author of the new paper. “It was very gratifying to see an effect on both the brain’s electrical activity and the animals’ behavior.”

Abnormal activity of NMDA receptors has been long implicated in neuropsychiatric, epileptic, and neurodegenerative disorders. But previous compounds for altering NMDA receptor function worked by binding to all subtypes of NMDA receptors, and either completely blocked the receptors or put them in a permanently active state. Researchers have theorized that modulating the receptors only at active synapses may help diverse cognitive diseases by potentiating synaptic function and increasing neuronal communication.

FANS Trial Testing Ketone Supplementation to Help Control Seizures in Children With Angelman Syndrome

A clinical trial is evaluating the safety and tolerability of a nutritional formulation containing the ketone beta-hydroxybutyrate (BHB) as a treatment to help control seizures in children with Angelman syndrome.

More information about the trial, called Nutritional Formulation for Angelman Syndrome (FANS), is available here.

The protocol of this trial was described in a paper, titled “Evaluation of the safety and tolerability of a nutritional Formulation in patients with ANgelman Syndrome (FANS): study protocol for a randomized controlled trial,” published in the journal Trials.

Seizures that are resistant to medication are estimated to occur in more than three-quarters of people with Angelman syndrome (AS). Certain dietary interventions, the ketogenic diet in particular, have shown considerable efficacy at controlling these seizures. This diet involves eating very few carbohydrates (sugars and starches) and consuming more fats.

Generally, cells in the body will preferentially use carbohydrates — particularly glucose — as an energy source. When carbohydrates are unavailable, the body will instead use fat for energy in a process called ketosis. This process, in turn, generates molecules called ketones, such as BHB.

While it is not entirely known why ketones are beneficial, a number of hypotheses have suggested that ingesting ketones leads to a metabolic shift that results in increased inhibition of cell toxicity and ultimately to a dampening of overall neuron excitability and decreased seizure activity.

Although the “keto diet” can help control seizures, many people with AS experience digestive problems and difficulty in feeding, which make it difficult for them to adhere to the diet and get enough nutrition.

In the FANS trial, instead of going on a ketogenic diet, participants will be given a nutritional formulation that is directly supplemented with BHB. The idea is that directly consuming the ketones could produce similar benefits as a ketogenic diet, but be easier to manage.

The trial will be conducted in the Angelman Syndrome clinic at Monroe Carell Jr. Children’s Hospital at Vanderbilt University Medical Center (in Nashville, Tennessee) in collaboration with sponsor Disruptive Nutrition. The study is being funded by the Foundation for Angelman Syndrome Therapeutics (FAST).