Developing new biomarkers to support clinical trials in Dravet syndrome 

THE CONTEXT 

Dravet syndrome is a severe genetic form of epilepsy affecting roughly one in every 15,700 births. It is caused by mutations in the SCN1A gene, which directs the production of an essential component of the channels that allow brain cells to transmit their electrical signals. 

Children living with Dravet syndrome experience frequent, disabling seizures even when treated with three or four antiepileptic medications at once. But seizures are only part of the burden. Cognitive impairment, sleep disturbances, feeding difficulties, walking problems and a considerably increased risk of sudden unexpected death weigh heavily on these children and their families. 

The mortality rate associated with Dravet syndrome is estimated at 15 to 20%.] 

There is real reason for hope. Several promising therapies are in development and target the molecular mechanisms of the disease itself. Through approaches such as viral vector gene therapy and antisense oligonucleotides, these new treatments could not only improve seizure control, but also address the many non-seizure comorbidities associated with the condition. 

One major obstacle stands in the way. To demonstrate to regulatory authorities that a treatment works, clinical trials require reliable and meaningful outcome measures. Today, most Dravet syndrome trials rely on seizure frequency as their primary endpoint, sometimes supplemented by developmental and cognitive assessments. All of these methods have limitations. What is missing are biomarkers: objective, measurable indicators able to provide rapid and meaningful information about a patient’s true clinical state. 

THE PROJECT 

This project sets out to develop those biomarkers, starting from a central hypothesis: brain activity measured non-invasively through electrodes placed on the scalp correlates with the clinical status of children with Dravet syndrome. 

The team will first analyze electroencephalography (EEG) recordings from a cohort of at least 50 patients, aiming for a total of at least 200 recordings collected both retrospectively and prospectively. Patients will be recruited from Dr. Myers’ neurodevelopmental disorders database and biobank, in collaboration with CHU Sainte-Justine and with epilepsy genetics specialists practising at other centres across Canada. For each recording, clinical data will be gathered: age, sex, developmental quotient, seizure frequency and medication. 

Each EEG will undergo a quantitative frequency band analysis, performed separately for wakefulness and sleep. The primary measure under study is delta power, the intensity of the slowest brain activity, which the team will correlate with developmental quotient and seizure frequency. 

The project will then turn to magnetoencephalography (MEG), a cutting-edge technique still rarely applied to Dravet syndrome. Twenty patients will undergo MEG recordings at the Montreal Neurological Institute, in order to define the typical profiles of the disease, identify the brain regions showing slower or faster activity and, in patients who present them, localize the source of the electrical discharges that signal a predisposition to seizures. 

OBJECTIVES 

1. Assess the correlation between delta power, other quantitative parameters derived from scalp EEG, and clinical status within a cohort of patients with Dravet syndrome; 
2. Define the typical magnetoencephalography profiles of patients with Dravet syndrome; 
3. Assess the correlation between electrophysiological measures obtained through MEG and patients’ clinical status. 

WHAT MAKES THIS PROJECT ORIGINAL 

EEG studies using advanced quantitative techniques remain very limited in Dravet syndrome, and none has been conducted at the scale proposed here. As for MEG, the team is aware of only one previous study: presented at a conference, it was never published in a peer-reviewed journal and did not take patients’ clinical status into account. 

POTENTIAL IMPACT ON CHILDREN’S HEALTH 

This study could significantly improve the lives of children with Dravet syndrome worldwide. By identifying reliable biomarkers that can be used in clinical trials, it would remove one of the main obstacles to developing new therapies for this devastating disease. 

The magnetoencephalography analysis should also deepen our understanding of the precise nature of the brain dysfunction associated with Dravet syndrome, potentially opening the way to better-targeted treatments. 

POTENTIAL IMPACT ON STUDENT TRAINING 

This study will form the core project of a master’s student enrolled in McGill University’s Integrated Program in Neuroscience, who will gain an in-depth understanding of electrophysiology and its relationship to brain function in people living with developmental and epileptic encephalopathy. Medical students and resident physicians will also take part in patient recruitment and testing, gaining hands-on experience with essential clinical research techniques.