Following treatment, children experienced fewer seizures and demonstrated improved communication and other developmental skills – outcomes not generally possible with typical antiseizure medications.

Researchers at Cook Children’s played a key role in the clinical trials that led to these findings, which were published in a March 2026 article in the New England Journal of Medicine (NEJM). Pediatric epileptologist M. Scott Perry, M.D., head of Neurosciences and director of the Justin Institute at Cook Children’s, co-authored the article and served as the lead investigator for one of the pivotal studies.

Dravet syndrome affects about 20,000 people in the United States. It causes seizures and problems with speech, sleep, development, intellectual abilities and more. About 100-125 patients from across the country come to Fort Worth seeking out Cook Children’s nationally recognized expertise in Dravet syndrome care.

Two initial studies – called MONARCH and ADMIRAL – enrolled 81 patients at multiple sites, including four patients at Cook Children’s. Two extension studies – SWALLOWTAIL and LONGWING – enrolled 75 patients. Dr. Perry served as lead investigator of SWALLOWTAIL.

The primary purpose of the studies was to assess the safety of zorevunersen, a medication administered via spinal tap. Participants received different amounts to help determine an optimal dosage that works safely and effectively.

The results are exciting, Dr. Perry said, because they indicate zorevunersen modifies Dravet syndrome by targeting the root cause. Study participants had fewer seizures and improvement in decision making, social interaction, communication, motor skills and other adaptive behaviors. 

“We have a treatment which at least in early phase studies shows the potential to address the underlying genetic reason for the condition and as a result bring about improvements in the symptoms and frankly change the course of the condition for the patient, which is a considerable advancement over what we currently have available,” Dr. Perry said. 

Adverse side effects were mostly mild or moderate, including elevated protein in the cerebrospinal fluid and pain after the spinal tap procedure.

Understanding Dravet

Most people diagnosed with Dravet syndrome have a mutation in the SCN1A gene that disrupts the production of normally functioning sodium channel proteins in the brain. The sodium channel is essential for neurons to fire appropriately. Seizures occur when the electrical flow misfires.

Antiseizure medication is currently the standard of care. But antiseizure medications don’t always control the seizures. And even when the frequency of seizures drops off, the patient’s cognitive delays and other symptoms don’t necessarily improve. 

“Dravet is a condition called a developmental and epileptic encephalopathy, which means the seizures themselves cause problems, but the underlying reasons for the seizures also cause problems,” Dr. Perry said. “This drug aims to address that by treating the actual genetic abnormality. And when you correct the gene that causes the problem, now you can improve seizures and the nonseizure symptoms that come with it.”

While one copy of the gene produces good proteins, Dr. Perry explained, the mutated version found in Dravet makes proteins that don’t function effectively. Zorevunersen is a precision medicine that capitalizes on the healthy copy of SCN1A.

How does it work? Ribosomes are the part of the cells that read messenger RNA (mRNA), which Dr. Perry described as the recipe that forms the sodium channel. Zorevunersen prompts the ribosomes to skip over the portion of mRNA that discards both healthy and unhealthy copies of the gene. No longer discarded, more healthy copies are available to create more functioning sodium channel proteins.  

Methods and Findings

Patients with Dravet syndrome from ages 2-18 years participated in the MONARCH, ADMIRAL, SWALLOWTAIL and LONGWING trials beginning in June 2020. Eighty-one percent of participants were taking three or more antiseizure medications prior to their first dose of zorevunersen.

The main objective was evaluating the safety of the trial therapy. Patients received one or more doses ranging from 10 milligrams to 70 mg. Data showed a reduction in seizures compared to the patients’ baseline numbers.  

“What we determine from these studies is that initial doses of 70 mg performed better than any of the lower doses,” Dr. Perry said. “People who got multiple doses of 70 mg did better than people who got single doses. People who got two doses of 70 mg did similarly to people who got three. That’s why we’ve chosen two 70 mg doses as the loading dose for the ongoing phase 3 clinical trial.” 

Participants in the extension studies followed up by receiving doses up to 45 mg every four months. At that level, they continued to maintain the similar reduction in seizures, he said.

Changes in adaptive behaviors and quality of life were measured by various scales based on impressions from clinicians and caregivers. Improvements were reported across the board. 

Biotechnology company Stoke Therapeutics, Inc. opened the next phase of the trial, called EMPEROR, in August 2025. Participants will receive either zorevunersen or no treatment in four spinal taps over a 52-week period.

Dr. Perry said inclusion in the NEJM article shows Cook Children’s is making a significant contribution to a big advancement in Dravet syndrome care. By joining clinical trials, research sites help find solutions and hope for patients with complex conditions.

“Cook Children’s does meaningful research. This is clinical trial work developing novel new therapies for devastating diseases,” he said. “Cook Children’s played a key role in the development of this treatment, and the NEJM is an incredibly prestigious journal. It’s a big deal for Cook Children’s to be a major contributor to such a huge contribution to science.”

RELATED STORIES:
Groundbreaking trial targets genetic cause of epilepsy
Precision medicine: Clinical trial treats rare type of epilepsy

Bridging Innovation and Patient Care

Backed by over 20 years of translational research experience and with 100+ peer-reviewed research investigation articles under his belt, Dr. Papadelis brings a wealth of scientific expertise to this partnership, all driven by compassion for people. 

“What I like to see with my research is how to help children,” Dr. Papadelis said. “That's why I like what's called translational research. It's not science for the sake of science. It's science for the sake of applying the knowledge to help somebody.” 

Both organizations provide critical assets for translational research, which is the bridge connecting basic discoveries to the application of those discoveries within patient care. 

“UTA has been active in translational research for a long time, but we want to expand in big ways,” Dr. Weidanz said. “I think Dr. Papadelis and this growing partnership with Cook Children’s is really setting all of that in motion. It’s really unique that we can bring the best of both worlds together so that we both excel in translational medicine. It’s a win for all of us, and most importantly, for patients.” 

With its brain-trust of academic researchers, including doctoral and postdoctoral candidates, as well as leading-edge laboratories and technology, UTA provides the infrastructure for imagination-driven discovery that could lead to breakthroughs in treating rare and complex neurologic conditions in children. 

Cook Children’s diverse patient population offers UTA researchers an expanded pool of potential study participants. In addition, the health system’s vast network of clinical experts, who understand the unique needs and challenges of pediatric health care, can apply and evaluate research findings in real time within their care settings. 

“Our department is a support system for this work,” said Luke Hamilton, Cook Children’s director of Clinical and Translational Research. “Our scientists have expertise in translating data produced from clinical encounters, aggregating, and analyzing for findings to create a new evidence base that can be fed back to our clinicians and improve clinical care."

A Ripple Effect

Along with enhancing Cook Children’s ability to deliver evidence-based innovation in patient care, this collaboration boosts both organizations’ ability to attract competitive federal funding, postdoctoral talent and joint appointments, which increases their visibility in academic publishing and conference networks. 

The local economy could score big, too. 

“We shouldn't overlook economic development and the impact we can have on growing our community,” Dr. Weidanz said. “I think these collaborations, starting with Dr. Papadelis and looking forward to what comes next, could eventually lead to the commercialization of some of these new findings, and that translates to jobs. Of course, we’ll never lose sight of the patient, but these partnerships really help the community flourish."

From Ancient Cities to the Western Frontier

Born in Athens, Greece, and raised in Thessaloniki, Dr. Papadelis parlayed an electrical engineering diploma from Aristotle University into a career studying the electrical pathways of the pediatric brain, taking special interest in epilepsy and movement disorders such as cerebral palsy. 

“I found that engineers like objects, but they don't like communicating with people,” Dr. Papadelis said. “I'm a very extravagant personality. I like to connect with people, and I talk a lot, so I realized I didn't belong there. But the engineering school gave me knowledge of how to use engineering skills in health care to help physicians. That’s when I went for a master’s and Ph.D. in biomedical engineering. I found my spot there and realized there is so much technology and tools that we can use to help physicians, and this is what I found fascinating.” 

In his prestigious career, Dr. Papadelis has lived and worked in five cities throughout four different countries across three continents. At the RIKEN Brain Science Institute in Japan, he honed his skills in the neuroimaging technique known as magnetoencephalography (MEG)—the fastest brain imaging tool available, allowing doctors to see brain activity in real time. In Trento, Italy, Dr. Papadelis marveled at his daily view of the Italian Alps while completing a post-doctoral fellowship at the Center for Mind/Brain Sciences at the University of Trento. 

In 2011, the neuroscientist made his way across the pond for his first faculty appointment—a professorship teaching neurology at Harvard Medical School. He also joined the research staff of Boston Children’s Hospital, where he led the development of its clinical MEG laboratories and programs. 

Cook Children’s invited Dr. Papadelis to join the health system in 2019. His heart for connection made him the perfect fit for a health system whose promise to do everything for the child is fueled by kindness, collaboration and imagination. The prospect of warmer weather made the offer all the more attractive. 

“I was looking for a change in my career, and I decided to give it a try,” Dr. Papadelis said. “I moved down here with my family, and we love it. We felt really welcome. Being Greek, I feel like I belong in the south because I like the weather.” 

Dr. Papadelis was first named Cook Children’s founding director of Research within its Neurosciences program. In September 2024, he became the assistant vice president of Research at the newly opened Jane and John Justin Institute for Mind Health at Cook Children’s. The Cook Children’s team he leads includes several UTA faculty members, postdoctoral researchers, alumna and research assistants, as well as a host of UTA doctoral students. 

Since arriving in North Texas, Dr. Papadelis has led Cook Children’s to new heights with several “firsts” for the health system. These include Cook Children’s receiving its first research grant from the National Institutes of Health, securing its first patent, and achieving its first fully approved Institutional Review Board (IRB) protocol for using Transcranial Magnetic Stimulation in conditions like cerebral palsy. 

While his research covers a broad range of studies in neuroscience, clinical neurophysiology and biomedical engineering, Dr. Papadelis’ main goal is to develop a novel epilepsy biomarker that will help children with drug-resistant epilepsy become seizure-free after resective neurosurgery, and he’s well on his way. Under his leadership, Cook Children’s Neurosciences research team has uncovered several new signs for identifying the epileptogenic zone with high precision, and developed new AI tools for predicting surgical outcomes in children with drug-resistant epilepsy. These discoveries and prediction tools help guide physicians in their treatment, improve the accuracy of surgical interventions, and give new hope to patients with uncontrolled seizures. 

“Cook Children’s is not just a hospital that takes care of the children in the region,” Dr. Papadelis said. “We develop here, and we perform very innovative research that has been recognized nationally and internationally by the scientific community.” 

Shortly after joining Cook Children’s, Dr. Papadelis also joined UTA’s faculty as a professor of Bioengineering. From that relationship grew the framework for the Pediatric Brain Health and Neurosciences Center partnership. In addition to his Cook Children’s team, Dr. Papadelis oversees a 16-member research team at UTA, while also mentoring several doctoral and postdoctoral candidates. 

“Dr. Papadelis is an incredibly passionate, creative and curious scientist with an eye on delivering his research findings to the patient,” Dr. Weidanz said. “He laid the groundwork for what’s to come, and that is a very strong partnership between UTA and Cook Children’s.” 
 

Running around too much or getting too hot used to trigger seizures several times a week for 8-year-old Sebastian Ruiz.

But since he started new investigational treatment through a clinical study at Cook Children’s, the seizures happen less often -- once or twice a month – and don’t last as long, Sebastian’s mom said.

Sebastian is one of about 20,000 people in the United States with a rare form of epilepsy called Dravet syndrome. Along with seizures, the disorder also leads to problems with speech, sleep, development and intellectual abilities among other issues. Sebastian was diagnosed with Dravet syndrome at 15 months old.

Juan and Rainey Ruiz make the two-hour drive from their home in Rosebud, Texas, to Cook Children’s Medical Center in Fort Worth so that their son can receive a new treatment still in the trial stage. That medication, called zorevunersen, works to offset the genetic malfunction that causes Dravet syndrome.   

Rainey Ruiz said Sebastian used to have seizures that sometimes lasted from 30 minutes to an hour. Other medications weren’t helping. Now he receives a dose of zorevunersen every four months via spinal tap as part of the SWALLOWTAIL study. Rainey is grateful Sebastian has the chance to try an innovative therapy.

“When you’re a mom, you’re just desperate for anything and hope you’re doing the right thing,” she said. “It’s hard for me to be content with where we are and not try for something better for him.”

The U.S. Food and Drug Administration in December 2024 granted the medicine a breakthrough therapy designation as a potential disease-modifying treatment for Dravet syndrome. In Dravet syndrome, one of the two copies of the SCN1a gene has a variant, or change that impairs the genes ability to make a normally functioning sodium channel. The sodium channel is essential for the brain's neurons to fire appropriately. Zorevunersen is designed to capitalize on the healthy copy of SCN1a, helping it produce more functional sodium channel proteins in the brain, addressing the disorder’s root cause rather than just treating its symptoms.

Biotechnology company Stoke Therapeutics, Inc. opened a third phase of the trial, called EMPEROR, in August 2025. M. Scott Perry, M.D., epileptologist and head of the Justin Institute at Cook Children’s, serves as lead investigator at Cook Children’s. The trial across approximately 70 sites involves 170 children and teens who have the SCN1A gene variant responsible for Dravet syndrome. The goal? To assess the medication’s safety and its impact on seizures, communication and other areas.

Patients enrolled in the EMPEROR trial undergo four spinal taps over 52 weeks, the first two 8 weeks apart and each additional procedure every 16 weeks. Patients will either get zorevunersen or no treatment during the 52-week period. The trial’s first patient from Cook Children’s received their initial dose in September 2025. 

Dr. Perry said patients in SWALLOWTAIL and other earlier phases experienced fewer seizures, less severe seizures and improved ability to communicate and interact, as well as improvements in motor skills.  

“The disease-modifying therapy is trying to correct the underlying cause,” Dr. Perry said. “And if you can correct the underlying cause or at least lessen the underlying cause’s impact, then you can have improvement across multiple manifestations of the disease.”

How It Works

Most people with Dravet syndrome have a mutation in the SCN1A gene that disrupts the production of normally functioning sodium channel proteins in the brain, causing abnormal electrical flow that leads to seizures. While one copy of their gene is producing good proteins, Dr. Perry explained, the mutated version is producing proteins that don’t work effectively. 

Ribosomes are the part of the cells that read messenger RNA (mRNA), which Dr. Perry described as the recipe that makes up the sodium channel. Zorevunersen prompts the ribosomes to skip over and not read the portion of the mRNA that destroys both healthy and unhealthy copies. Because they’re not being discarded anymore – a natural process to limit overproduction of proteins -- more healthy copies are available. As a result, more functioning sodium channel proteins can be created.  

“You end up basically getting almost 100% of the healthy version through to make up for what you’re losing on the unhealthy side,” Dr. Perry said.

Cook Children’s treats about 100-125 Dravet syndrome patients from across the country. As a recognized leader in epilepsy care and research, Cook Children’s was the initial site Stoke Therapeutics visited ahead of the EMPEROR trial. Cook Children’s Neuropsychology, Neurodiagnostics, Anesthesiology, Radiology and MRI departments are involved as well.

“I think it underscores what is possible at Cook Children’s from a research standpoint,” Dr. Perry said. “That is not a simple trial. It’s quite complex in its design. Cook Children’s was selected to participate because we can do it well. We have a track record of doing it well.”

Current options in doctors’ toolkits focus on treating the seizures, he said. Other symptoms, such as speech, still present problems. Zorevunersen gives doctors hope that precision medicine will change the genetic factors behind Dravet syndrome so that patients see improvement across the board.

Spotlight on Sebastian

Sebastian had his first seizure at 4 months old and the next one three months later. They happened more frequently after that, and sometimes he had to be intubated at the hospital during a seizure. He started coming to Cook Children’s at age 2 years when the Ruiz family sought out a neurologist who specialized in Dravet syndrome. 

“Dr. Perry is the top. He’s amazing,” Rainey said. 

Sebastian had been enrolled in several clinical trials prior to SWALLOWTAIL. Now a third-grader, Sebastian has limited ability in speech, but he recently started recognizing letters of the alphabet. He loves basketball, school and his four siblings. Running a fever, overheating or overstimulation can still bring on seizures -- but not as often since he started the zorevunersen therapy, his mom said.

Participating in clinical trials can be long and hard, and there’s no guarantee the medication will benefit your child, Rainey pointed out. But trials provide hope for better outcomes for patients in the future. She encouraged parents of Dravet syndrome patients to consider enrolling if that’s an option for them.  

“It’s just hard for me to stand by and not try to do something,” she said. “Even if it helps other kids, it’s still a win-win. You can change lives in other ways.”

RELATED STORIES:
Groundbreaking Trial Targets Genetic Cause of Epilepsy
A Mother’s Intuition, a Doctor’s Care

Their findings were published in March 2025 in the top-tier scientific journal Nature Portfolio Journal Digital Medicine. The article explains how the research team designed and trained a machine-learning tool to specifically locate the seizure starting point in children and teenagers.

During their two-year study, the researchers came up with an automated system that works by analyzing recordings of electrical activity in the brain. The researchers entered the data into the framework, and the system learned to identify where the drug-resistant seizures started.

“The system provides as an output to the epileptologists and neurosurgeons the brain area to resect in order for the patient to become seizure free,” said Christos Papadelis, Ph.D., Assistant Vice President of Neuroscience Research at the Jane and John Justin Institute for Mind Health at Cook Children’s Health Care System.

Dr. Papadelis teamed up with his postdoctoral research fellow Hmayag Partamian, Ph.D., to come up with the project’s concept and experimental design. Dr. Partamian developed the mathematical formulas and codes. The work took place in labs at Cook Children’s Medical Center in Fort Worth and at the University of Texas at Arlington, where Dr. Papadelis serves as Professor of Research in Bioengineering and Director of the Pediatric Brain Health and Neurosciences Center.  

The study utilized data from 43 children with drug-resistant epilepsy who underwent resective surgery. The goal of resective surgery is to stop seizures from occurring by removing the brain tissue where the seizures originate.  

Dr. Papadelis said the new AI-based tool could help improve the outcome of those surgeries by precisely defining which tissue to remove, giving those patients hope for a seizure-free future.

Where Seizures Begin

Nearly 500,000 children nationwide live with the chronic disorder of epilepsy. They suffer from seizures, which are misfiring of electrical activity in the brain. Someone experiencing a seizure might have a blank stare, muscle spasms, or loss of consciousness. Medications control seizures in about 70% of epilepsy patients. The others have what’s called drug-resistant epilepsy. 

The AI tool created by Dr. Papadelis and his team requires just five minutes of recorded brain electrical activity to determine the area of seizure origin. This presents a significant advantage compared to conventional methods that typically require recording the brain activity for several days -- or even weeks -- in order to capture a seizure.

The tool then transforms the electrophysiological data into color-coded maps of brain activity across time and corresponding these maps into active epileptic regions in the brain. Researchers trained the AI tool to automatically discriminate epileptic from healthy brain regions in these maps. Surgical resection of the epileptic regions in these brain maps can predict a good prognosis for the patient.

Dr. Papadelis pointed out important features of the automated process:

• Less chance for human error from manual interpretation of the data
• Reduced costs, time and risks from the presurgical evaluation process

“We have developed an AI, patient-specific method that automatically identifies the brain area that generates seizures in patients with drug-resistant epilepsy. This method requires little to no input from clinicians,” Dr. Papadelis said. “Our method eliminates the need for manual data inspection, reduces prolonged monitoring and enhances surgical planning.”

The study is in collaboration with Boston Children’s Hospital and is funded by a grant from the National Institute of Neurological Disorders and Stroke.

Dr. Papadelis plans to seek extra funding for the study’s next phase: applying the tool prospectively to patients who are candidates for surgical intervention at Cook Children’s.

Dr. Papadelis believes that the findings of this study represent a significant step toward improved surgical procedures for drug-resistant epilepsy.

“Such a framework would be particularly useful to epilepsy centers that lack the multidisciplinary expertise to delineate accurately and precisely the epileptogenic brain regions in complex cases,” the article states.  

Dr. Papadelis credited the dedication of all the researchers, and in particular he highlighted Dr. Partamian’s talent for scripting. The study shows direct benefits that align with the Cook Children’s Promise to improve the well-being of every child in our care and communities, he said.

“This is one of the moments that makes you feel really proud of the work that you have accomplished together with your team,” he said. “We keep our Promise to do our best for improving the lives of children suffering from devastating neurological disorders.” 

RELATED STORIES:
Cook Children’s Neuroscience Research Published in Brain Journal for 2nd Time This Year
History in the Making: Cook Children’s Secures NIH Grant
Cook Children’s Lead Neurosciences Researcher Addresses Congress Members on Capitol Hill

Cook Children’s recently participated in multicenter studies of the drug in treatment of patients with Dravet syndrome and is currently enrolling patients in a study for Lennox Gastaut Syndrome.

The research trials sponsored by Zogenix focus on a low-dose, liquid solution of fenfluramine, which was previously used in “fen-phen” for obesity and ultimately taken off the market following evidence it was related to adverse effects on heart valves.

Dravet syndrome affects an estimated 20,000 patients in the United States. Dravet results in a severe epilepsy with seizures typically resistant to treatment with currently available therapies.

The trial found that fenfluramine reduced the frequency of convulsive seizures by a median 62.7 percent, compared with a 1.2 percent median reduction in patients taking placebo, meeting the main goal of the trial.

Dr. M. Scott Perry, medical director of Neurology and Director of the Genetic Epilepsy Clinic at Cook Children’s said, “This drug is a game-changer for patients suffering from Dravet Syndrome. Rarely do we get a treatment for epilepsy which reduces seizures so significantly, especially in an epilepsy syndrome that is this refractory to therapy. I can’t wait to see if the results are as remarkable for Lennox Gastaut Syndrome.”

Thus far, no significant cardiac valvulopathy or pulmonary hypertension has been noted in trials for epilepsy, possibly due to the lower dosing used in these trials.

Zogenix will now focus on submitting applications for a marketing approval of its drug in the U.S. and Europe in the fourth quarter of 2018.