Findings From Comprehensive Drug Repurposing Screening To Treat Epileptic Encephalopathy Published In Epilepsia

Pairnomix, LLC announced on March 26, 2018 that results from a comprehensive drug repurposing screen performed for a patient with SCN8A epilepsy were published as an original research article online and in an upcoming print issue of Epilepsia, the official journal of the International League Against Epilepsy (ILAE) and a leading, authoritative source for current research results on all aspects of epilepsy.

The study, A Comprehensive Approach to Identifying Repurposed Drugs to Treat SCN8A Epilepsy details rigorous efforts to identify repurposed drug options for a patient with epileptic encephalopathy caused by the SCN8A R1872Q genetic mutation. Whereas most drug repurposing studies focus on one or a few select compounds, this research highlights a broader approach using high-throughput technologies to screen hundreds of on-market drugs in a single experiment. In this study, 90 drugs were identified to have a significant effect in cellular studies; the majority of these drugs have never been implicated as having effects on ion channels or epilepsy and therefore represent potentially novel mechanistic activity.

Gregory Stewart, PhD, Chief Scientific Officer at Pairnomix, remarked, “We are very pleased to share these results and the research approach we have undertaken to identify drug options for physicians to consider in their medical management of patients with the SCN8A R1872Q variant. Our work demonstrates the utility of comprehensive, high-throughput drug screens to identify new drug options for patients that are available for immediate clinical use.”

Findings From Comprehensive Drug Repurposing Screening To Treat Epileptic Encephalopathy Published In Epilepsia

Pairnomix, LLC announced on March 26, 2018 that results from a comprehensive drug repurposing screen performed for a patient with SCN8A epilepsy were published as an original research article online and in an upcoming print issue of Epilepsia, the official journal of the International League Against Epilepsy (ILAE) and a leading, authoritative source for current research results on all aspects of epilepsy.

The study, A Comprehensive Approach to Identifying Repurposed Drugs to Treat SCN8A Epilepsy details rigorous efforts to identify repurposed drug options for a patient with epileptic encephalopathy caused by the SCN8A R1872Q genetic mutation. Whereas most drug repurposing studies focus on one or a few select compounds, this research highlights a broader approach using high-throughput technologies to screen hundreds of on-market drugs in a single experiment. In this study, 90 drugs were identified to have a significant effect in cellular studies; the majority of these drugs have never been implicated as having effects on ion channels or epilepsy and therefore represent potentially novel mechanistic activity.

Gregory Stewart, PhD, Chief Scientific Officer at Pairnomix, remarked, “We are very pleased to share these results and the research approach we have undertaken to identify drug options for physicians to consider in their medical management of patients with the SCN8A R1872Q variant. Our work demonstrates the utility of comprehensive, high-throughput drug screens to identify new drug options for patients that are available for immediate clinical use.”

Human interest story: New Brain Implant Technology is Life Changing for Patient with Epilepsy

With one glance, you would never guess what 25-year-old Aimee Buckley of Pocatello, Idaho, has been through.

She was diagnosed with epilepsy when she was 8 years old. Seizures became her routine. “I’ve lived with them almost my entire life,” Buckley said.

Her father, Lynn Buckley, said it was tough. “There literally was one year where she hardly got out of bed,” he said.

She tried every treatment her doctors offered, but nothing worked. Unfortunately, the medications she tried made her sick. At age 14, Aimee Buckley underwent resective brain surgery removing part of her brain tissue, but to no avail.

Finally, Intermountain Healthcare’s Dr. Tawnya Constantino at Intermountain Medical Center offered Aimee Buckley a new treatment called RNS, or responsive neurostimulation. In 2016, a neurosurgeon implanted the device into her skull. “When the device detects that seizures are starting, it actually administers a stimulation to that electrode in an attempt to stop the seizures from developing,” Constantino said.

Constantino said the NeuroPace option seemed like a good fit for Buckley because Dr. Constantino had already identified the general location causing Buckley’s seizures, making it easier to prevent further seizure activity. “They don’t feel it going off. They don’t hardly know it’s there,” Constantino said.

Since then, Buckley is proud to say she has almost been seizure free. She had a couple minor seizures she was not aware of but were recorded on her device.

First Patient Enrolled in Cavion Multi-Center Phase 2 Clinical Trial in Epilepsy

Cavion, Inc. announced March 20th that the first patient has been enrolled in its innovative T-WAVE Phase 2a proof-of-concept clinical trial (NCT03406702). T-WAVE will assess the safety, tolerability and efficacy of the T-type calcium channel modulator CX-8998 in drug-resistant absence seizures in adolescents and young adults with generalized epileptic syndromes.

Generalized epileptic syndromes are associated with abnormal activity of selected neural networks. T-type calcium channels, called Cav3, control neuronal firing and signaling. Cav3 is a strong genetic target as gain-of-function Cav3 mutations have been identified in patients with generalized seizures. CX-8998 is a first-in-class oral therapeutic drug that was designed to selectively and potently inhibit Cav3 channels, repairing aberrant neuronal activity. Data from genetic preclinical models of generalized epilepsy suggest that CX-8998 suppresses epileptiform discharges and prevents the development of seizures, including absence seizures.

Cavion has deep expertise advancing the science of Cav3 modulation in white-space central nervous system indications with high unmet need. T-WAVE leverages Cavion’s unique clinical development engine that delivers insightful data using cutting edge digital biomarkers and artificial intelligence while collaborating with advocacy groups to put patients and their families at the forefront, said Spyros Papapetropoulos, Cavion’s Executive Vice President, Head of Research & Development and Chief Medical Officer.

New treatment options to control generalized seizures and maintain quality of life for patients and their families are particularly needed, as there are limited options currently available. New treatments for generalized epilepsy would provide a significant opportunity to help adolescents and young adults, said Dr. Jacqueline French, Chief Scientific Officer at the Epilepsy Foundation and Professor of Neurology at NYU School of Medicine.

Human interest story: Girl is Seizure Free After Treatment for Autoimmune Epilepsy

In the Fall of 2010, Toya and her husband Dr. Anthony Johnson, pastor at Prayer Temple Missionary Baptist Church in Redford, Michigan, were getting ready to go to church. Their plans took a dramatic turn when their 5-year-old daughter, Alyse, had the family praying on their way to a local emergency department after her body started shaking, her eyes rolled back and her mouth shifted to one side.

After two weeks of seizures, doctors prescribed an anti-seizure medication, but Alyse still had seizures daily. She was treated for epilepsy with additional antiepileptic drugs (AEDs) and increased doses but her condition worsened. She started losing her ability to walk and talk.

In September 2014, Alyse was evaluated by Mitchel T. Williams, M.D., pediatric neurologist at the Children’s Hospital of Michigan, who specializes in the developing field of neuroimmunology and epilepsy.

“Inflammation plays a role in epilepsy. Anywhere from 10 to 20 percent of intractable focal epilepsy cases are due to an underlying autoimmune cause. That is a huge percentage,” says Dr. Williams.

After finding out that family members had autoimmune disorders, Dr. Williams suspected that in Alyse’s case, there was such an underlying cause making the steroids ineffective in fully addressing her issues.

Further testing showed that Alyse had seizure activity during 85 percent of her sleeping time. The treatment plan? Intravenous immunoglobulin (IVIG) for autoimmune epilepsy which involves administering a sterile solution of concentrated antibodies extracted from healthy donors into a vein. “IVIG does not suppress the immune system, it bolsters it,” says Dr. Williams. “You are gaining antibodies from many other people. It in essence tames the immune system and diffuses the abnormal response.”

Since her IVIG treatments over 3 year ago, Alyse takes fewer antiepileptic drugs and she continues her IVIG treatments twice a month at the Children’s Hospital of Michigan. Thanks to the success of the IVIG treatments, Dr. Williams has also weaned Alyse off the steroids which caused side effects such as weight gain and diabetes.

New Direction For Precision Medicine In Epilepsy

In a new approach to precision medicine research, scientists used bioinformatics tools to identify common features of genes associated with infantile spasms compared to other forms of early life epilepsy. Their analysis, published in PLOS ONE, reveals that infantile spasms are not only unique clinically, but also biologically. Focus on specific biological mechanisms underlying the genes that cause infantile spasms could help find new targets for treatment.

‘Our novel approach marks a paradigm shift in precision medicine from single gene discovery to grouping genes by their underlying biology,’ says lead author Anne Berg, PhD, epilepsy specialist at Ann & Robert H. Lurie Children’s Hospital of Chicago and Research Professor in Pediatrics at Northwestern University Feinberg School of Medicine. ‘To develop new treatments, we can start looking at mechanisms common to many associated genes, instead of trying to therapeutically target one gene at a time. With this approach, we are starting to ask why certain genes are involved, which might help us understand why some treatments are effective and others are not. Such an approach could ultimately help us choose the treatment that mostly precisely matches the genetic signature and biology of the child’s epilepsy.’

‘We used bioinformatics tools to perform what is called gene set enrichment analysis, which means that we looked at common molecular properties of genes that lead to infantile spasms and other types of seizures,’ says Dr. Berg. ‘We examined how these genes function in the cell, in what processes they are involved, where in the cell they are expressed. We found that the genes associated with infantile spasms are uniquely involved in developmental functions within the cell body, which might be linked to why spasms tend to start at the same time in an infant’s development.’

Study: KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy

Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151.

Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus.

Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.

Improved method for mesial temporal lobe epilepsy surgery: Automated trajectory planning for laser interstitial thermal therapy

Following laser interstitial thermal therapy for mesial temporal lobe epilepsy, computer-assisted planning provides a better safety profile, with potentially improved seizure-free outcome and reduced neuropsychological deficits, according to an Epilepsia study.

Objective: Surgical resection of the mesial temporal structures brings seizure remission in 65% of individuals with drug-resistant mesial temporal lobe epilepsy (MTLE). Laser interstitial thermal therapy (LiTT) is a novel therapy that may provide a minimally invasive means of ablating the mesial temporal structures with similar outcomes, while minimizing damage to the neocortex. Systematic trajectory planning helps ensure safety and optimal seizure freedom through adequate ablation of the amygdalohippocampal complex (AHC). Previous studies have highlighted the relationship between the residual unablated mesial hippocampal head and failure to achieve seizure freedom. We aim to implement computer-assisted planning (CAP) to improve the ablation volume and safety of LiTT trajectories.

Methods: Twenty-five patients who had previously undergone LiTT for MTLE were studied retrospectively. The EpiNav platform was used to automatically generate an optimal ablation trajectory, which was compared with the previous manually planned and implemented trajectory. Expected ablation volumes and safety profiles of each trajectory were modeled. The implemented laser trajectory and achieved ablation of mesial temporal lobe structures were quantified and correlated with seizure outcome.

Results: CAP automatically generated feasible trajectories with reduced overall risk metrics (P< .001) and intracerebral length (P = .007). There was a significant correlation between the actual and retrospective CAP-anticipated ablation volumes, supporting a 15 mm diameter ablation zone model (P < .001). CAP trajectories would have provided significantly greater ablation of the amygdala (P = .0004) and AHC (P = .008), resulting in less residual unablated mesial hippocampal head (P = .001), and reduced ablation of the parahippocampal gyrus (P = .02).

Significance: Compared to manually planned trajectories CAP provides a better safety profile, with potentially improved seizure-free outcome and reduced neuropsychological deficits, following LiTT for MTLE.

Biologists link protein, seizure suppression

Research shows that seizure suppression was associated with an increase in COX-2 expression in neurons.

James Hewett, associate professor of biology, and Yifan Gong, a Ph.D. candidate in biology and neuroscience, have co-authored an article in the journal Neuroscience (Elsevier, 2018) about a protein in the brain called T-cell intracellular antigen-1 (TIA-1).

“TIA-1 is known for its ability to regulate gene expression during cellular stress,” says Hewett, who studies the processes that suppress the severe electrical storms in the brain, leading to seizures. “We suspected that TIA-1 was involved with seizure suppression, but our findings suggested something else.”

He and Gong are interested in the function of an enzyme in the brain called cyclooxygenase-2 (COX-2). This enzyme makes prostaglandins — chemical messengers that aid in the performance of normal tasks, including learning and memory.

“Our findings raise the possibility that the level of neuronal COX-2 expression in the brain may be a determinant of the seizure threshold [a natural set-point for electrical activity, above which seizures occur]. This suggests that a better understanding of the regulation of COX-2 expression in the brain can provide new insights into molecular mechanisms that suppress seizure-induction,” adds Hewett, a pharmacologist by training.

Prof. Ley Sander Discusses Preventing SUDEP and How to Build Research Around SUDEP: Video from CURE Frontiers in Research Seminar Series

Video is available from the CURE Frontiers in Research Seminar Series talk given by Professor Ley Sander, discussing SUDEP prevention and research.

Talk summary: Individuals with epilepsy, particularly those with uncontrolled epilepsy, are at a much greater risk of premature death than those without. In fact, the standardized mortality ratio in those with epilepsy is between 2 and 3. In the UK, the most common cause of epilepsy-related death is due to Sudden Unexpected Death in Epilepsy (SUDEP), which accounts for up to one-fifth of deaths in some series. SUDEP is more common in those with frequent convulsive seizures (particularly nocturnal seizures) and in those with drug-resistant epilepsy. While the causes of SUDEP are unknown, the most commonly suggested underlying mechanisms are cardiac arrhythmias, respiratory depression and “cerebral shutdown.” Because no preventative measures currently exist, an understanding of SUDEP risk factors, potential mechanisms and the effectiveness of preventative measures is essential. To this end, there are a multitude of opportunities available in the field of SUDEP research and these opportunities will be interactively discussed during the presentation.