Dravet Syndrome Foundation

Identification of Behavioral Biomarkers in Children with DS: A Pilot Study In conjunction with University of Michigan, this pilot study seeks utilize AI and machine learning to identify subtle but measurable behavioral patterns that can serve as biomarkers for disease progression and treatment response in Dravet syndrome that would be undetectable using traditional observational methods. Researchers aim to define objective indicators of cognitive, social, and functional changes with the goal to improve clinical trial endpoints and enable more sensitive tracking of outcomes. Findings may support the development of better tools for evaluating therapeutic impact in patient populations.

1. In conjunction with Tel Aviv University and Institut de Génétique Moléculaire de Montpellier - Transformational Science Grant: Molecular Characterization of the Therapeutic Effect of Exogenous Nav1.1 - $150,000. 2. In conjunction with MIT and Harvard University - Research Grant: Base Editing for the Treatment and Prevention of Dravet Syndrome - $90,000. Details for each of these projects can be found at https://dravetfoundation.org/dsf-funded-research/

Award Supplement for Genetic Substrates and Physiological Triggers for Autonomic and Cardiac Abnormalities. This project investigates the genetic and physiological factors underlying autonomic and cardiac dysfunction in Dravet syndrome and closely related epilepsy disorders. The goal is to identify specific triggers and biological mechanisms that contribute to irregular heart rhythms and autonomic instability. Researchers are integrating genetic analysis with physiological monitoring to better understand risk factors. Insights from this work may inform strategies to predict, monitor, and reduce life-threatening complications for Dravet syndrome.

In conjunction with The Children's Hospital of Philadelphia, Base Editing for the Treatment and Prevention of Dravet Syndrome. This project aims to develop a precision gene-editing approach using base editing technology to directly correct disease-causing mutations at the DNA level using a mouse model of Dravet syndrome. The goal is to create a durable, potentially one-time treatment that can restore normal gene function without introducing double-strand DNA breaks. Researchers are working to optimize delivery systems, improve editing efficiency, and evaluate safety in relevant models. Ultimately, the project seeks to establish a foundation for preventive or early-intervention therapies that address the root genetic cause rather than managing symptoms.

Selective Activation of Hippocampal Parvalbumin Interneurons via Focused Ultrasound Neuromodulation for Seizure Suppression in SCN1A Mice. This project evaluates a non-invasive neuromodulation approach using focused ultrasound to selectively activate specific inhibitory neurons in the brain. By targeting parvalbumin interneurons in the hippocampus, researchers aim to reduce hyperexcitability and suppress seizures in Dravet syndrome. The study assesses feasibility, precision, and effectiveness in preclinical models, while also examining safety and durability of the response. The long-term goal is to develop a targeted, non-pharmacological intervention for seizure control.

Creating a biobank of patient-derived induced pluripotent stem cells. This project aims to establish a biobank of five unique lines of commercially-available induced pluripotent stem cells (iPSCs) from patient blood samples. The cellular reprogramming will be conducted by the Coriell Institute for Medical Research and samples will be housed and distributed through an additional partnership with the Orphan Disease Center at The University of Pennsylvania. Cell lines will be available to researchers in academic and for-profit research settings at a low cost, set to cover the long-term maintenance of the biobank effort.

Individuals with Dravet syndrome (DS) can have different disease courses, and there are important differences in how seizure and development affect them over time. Identifying the causes of variation within the patient population may be helpful in providing accurate prognosis and developing new treatments. This project will generate broad genetic data with whole genome sequencing on 500 individuals with DS. These genetic analyses will be paired with clinical data using pioneered novel methods to transform clinical information to a format that can be used for computational analysis. Finally, this project is built for data sharing - all biosample data, genomic data, and clinical data will be shared within the DS Community.

Despite recent advances in small molecule drug discovery, the majority of Dravet syndrome (DS) patients remain intractable and non-seizure symptoms are not addressed. This project aims to exploit an alternative therapeutic strategy that has been successful in mouse models: Medial Ganglionic Eminence (MGE) progenitor cell transplantation to restore healthy fast-spiking interneurons in DS patient brains. While transgenic mice have provided invaluable insights into seizures and some comorbidities associated with DS, mice have critical differences in physiology and neuroanatomy compared to humans and thus are not the most appropriate model to test a cell transplantation-based therapy. In contrast, this study will use rabbits, which are larger vertebrates, more similar to humans. The results of this large animal work will strengthen the preclinical foundation for future cell transplantation therapeutic strategies in DS patients.

The scientific understanding of how the SCN1A gene changes brain activity is rapidly evolving. This work will explore whether a brain cell that is integrally important in Dravet syndrome symptomatology has disruptions that lead to specific malfunctions. This work aims to determine how mutations in the SCN1A gene impact these cells' normally powerful ability to "put the brakes on" the brain when it is too active. We believe that the loss of this "brake" may lead to seizures, and our experiments may yield important clues about how to get it working again.

Current precision therapeutic clinical trials for Dravet syndrome (DS) utilize seizure frequency as the primary outcome measure, but using this alone to assess outcome does not capture the full array of challenges associated with DS. This project will focus on refining a set of clinician and caregiver-reported outcome measures previously created for CDKL5-deficiency disorder and piloting them in patients with DS. The overarching objective is to design valid and feasible outcome measures specifically for DS that represent the full range of the phenotype. The creation of the DS clinical severity assessment-clinician and caregiver (DS-CSA) will be a crucial step towards disease modifying clinical trial readiness in DS.

Mutations in the SCN1A gene most commonly cause reduced functioning of the Nav1.1 protein and lead to Dravet syndrome, a debilitating epilepsy disorder. However, a new class of SCN1A mutations causes excessive activity of Nav1.1. Individuals with these mutations exhibit an even more severe form of epilepsy as well as developmental delay and intellectual disability. This research group has generated the first mouse expressing a patient-derived mutation associated with this severe early-onset condition. In this fellowship, they will evaluate the novel mouse for neurological abnormalities, including seizures and movement disorders. Additionally, they will investigate the electrical properties of neurons. The overall goal is to understand the mechanism by which both reduced and excessive activity of Nav1.1 can cause epilepsy and to identify treatments for both disorders.

Individuals with Dravet syndrome (DS) suffer from severe seizures that cannot be completely controlled by medications. While most epilepsy research has focused on the more superficial brain regions that we know are prone to seizures, an improved understanding of the role of deeper brain regions in epilepsy may open the door to new therapies. The focus of this proposal is a deep brain region called the locus coeruleus, which sends noradrenergic projections throughout seizure-prone brain regions. The locus coeruleus is known as a "master regulator" that coordinates brain-wide states, such as reward and attention; this project will test the hypothesis that it also plays a critical role in seizures in DS using a mouse model of DS, to (1) determine the activity of noradrenergic neurons during seizures and (2) test whether their activation curtails seizures.

This project aims to establish a biobank of five unique lines of commercially-available induced pluripotent stem cells (iPSCs) from patient blood samples. The cellular reprogramming will be conducted by the Coriell Institute for Medical Research and samples will be housed and distributed through an additional partnership with the Orphan Disease Center at The University of Pennsylvania. Cell lines will be available to researchers in academic and for-profit research settings at a low cost, set to cover the long-term maintenance of the biobank effort.

Development of an AI-powered Dravet Syndrome Ontology. Although a significant amount of data for Dravet syndrome (DS) is available from model organisms and humans, methods to integrate and analyze these disparate data resources are limited in scale and functionality. Artificial intelligence (AI) methods such as ontologies and machine learning (ML) algorithms are ideal for complex analytics over big data to aid in knowledge discovery. Satya Sahoo, PhD has already applied a combined epilepsy ontology and ML approach to analyze data resulting in high accuracy classification models. These findings suggest that AI methods can be used for automated analysis of basic science and clinical literature to compare model systems and humans and indicate new experiments to characterize these relationships. A DSF Research Grant was awarded to Dr. Sahoo to extend the epilepsy ontology specifically for DS that together with ML algorithms can automatically index literature and enable analysis of data.

Cerebellar deficits as mechanisms for motor, cognitive, and social dysfunction in Dravet syndrome. In addition to frequent and severe seizures, most people with Dravet syndrome (DS) also suffer life-altering difficulties with coordinated movement/muscle control, autism-associated behaviors, and learning and memory. The cerebellum is a brain region known to be involved in movement, cognition/memory, and social behavior, but is understudied in DS. Preliminary data showed that Purkinje cells are hypo-active in a mouse model of DS. Similar hypoactivity of this cell type causes movement disorders and autism in other neurological diseases. A DSF Research Grant was awarded to Mackenzie Howard, PhD to utilize a novel mouse model of DS that has allowed the study of DS-related genetic mutations in this specific cell type and the link to changes in comorbidities often reported in DS.

Cerebellar deficits as mechanisms for motor, cognitive, and social dysfunction in Dravet syndrome. A DSF Research Grant was awarded to William Nobis, PhD to investigate if chronic exposure to the odorant 2-phenylethanol ("rose odor") will decrease mortality and improve neuropsychiatric comorbidities of DS through attenuation of extended amygdalar neuronal activation. Given the long history of odorant therapy in the treatment of seizures, as well as links between the areas of the brain that receive olfactory inputs having a role in control of respiration and seizure-related breathing dysfunction, there is potential for odorants that modulate these circuits to provide a non-invasive, well-tolerated means to decrease seizure-related death. Exciting preliminary data using a mouse model of DS suggests that mortality is reduced by chronic exposure to rose odor, and this study will build on that data to explore the effects on mortality, seizure frequency and comorbidities.

Genetic Substrates and Physiological Triggers for Autonomic and Cardiac Abnormalities in Dravet Syndrome. Using cellular and animal models, David Auerbach, PhD previously demonstrated that Dravet syndrome (DS) mutations result in electrical disturbances in the heart, and cardiac arrhythmias preceded Sudden Unexpected Death in Epilepsy (SUDEP). Patients DS are at a high risk of SUDEP. A DSF Clinical Research Grant was awarded to Dr. Auerbach to perform detailed ECG analysis in two severe forms of epilepsy (DS & Lennox-Gastaut Syndrome) during specific non-seizure physiological states and investigate the temporal evolution of these measures leading up to and following a seizure, which will foster the future development and validation of ECG markers for cardiac-mediated SUDEP risk in DS patients.

Evaluating the effects of sub-chronic exposure to sub-clinical levels of CO on Dravet etiology and associated SUDEP risk. Carbon monoxide (CO) is one of the top most deadly air pollutants that is positively associated with an increased risk of epilepsy hospitalizations and sub-clinical seizures. CO is known to cause hypoxemia, hypoxia and impair lung function. Dravet syndrome (DS), a debilitating pediatric genetic epilepsy is characterized by refractory seizures, increased mortality rate due to sudden unexpected death in epilepsy (SUDEP), and cognitive/psychomotor dysfunction. SUDEP has no clear mechanisms but is reported to be caused by cardio-respiratory mechanisms. A DSF Postdoctoral Fellowship was awarded to Ashwini Sri Hari, PhD to address the question of whether and how CO exposure exacerbates pathomechanisms in DS patients and their associated SUDEP risk.

Targeting Molecular Responses to Seizures in Dravet Syndrome- Dr. Wagnon's work previously identified that the gene Npas4 is reduced in a mouse model of Dravet syndrome. This project hypothesized that restoration of high Npas4 expression could ameliorate seizures and other symptoms using viral-mediated delivery of Npas4 to the brain of mice with SCN1A haploinsufficiency.

Ketogenic Diet Modulated Brain Energy Metabolism in Dravet Syndrome- Dr. Thio and Dr. Garbow work together on this collaborative project to better understand the mechanisms whereby the ketogenic diet reduces seizures in Dravet syndrome. They will investigate two metabolic pathways in a genetic mouse model of Dravet syndrome and use neuroimaging techniques to assess these impacts within the brain.

Lymphoblast Cell Lines as a Model to Uncover Metabolic Defects in Dravet Syndrome- Dr. Patel and Dr. Knupp work together on this collaborative project to establish lymphoblast cell lines from the blood of patients with Dravet syndrome and their unaffected siblings. This library of cell lines will then be used to investigate alterations in energy metabolism that may impact patients with Dravet syndrome as well as stand as a future resource for investigations of new drugs, diets, and treatment responses.

Optimizing the Regional Administration of SCN8a-targeting RNAi Therapy- Dr. Yu's project worked to develop an AAV-delivery for a genetic-based therapy targeting the SCN8A gene. While the majority of cases of Dravet syndrome are caused by mutations in SCN1A, Dr. Yu and the Meisler lab have shown that using genetic-based therapies to reduce expression of the SCN8A gene can compensate for loss-of-function SCN1A-mutations that cause Dravet syndrome.