DSF was established around a central mission of advancing research for Dravet syndrome. A key way in which DSF accomplishes this mission is our yearly grant application cycle. At the 2023 Research Roundtable, DSF proudly announced the allocation of an impressive $2.475 million to eight grants, bringing the total amount that DSF has directed to Dravet-related research to over $9.2 million.
In addition to the five standing yearly grant categories, in 2023 DSF also announced a special request for applications focused on increasing our understanding of the impact of genetic background on the clinical presentation of patients with Dravet syndrome, expanding beyond the SCN1A gene. DSF has awarded an impressive $1 million to a grant from researchers Ingo Helbig, MD and Ethan M. Goldberg MD, PhD of The Children’s Hospital of Philadelphia. They will not only investigate this question in a large cohort of patients, but will simultaneously create rich databases of genetic and clinical information that could be useful to answer future research questions and facilitate collaboration in the field.
DSF also added a fifth category in 2023 to our standing grant program titled Transformational Science Grants. This grant category funds up to $500,000 distributed over five years to expert researchers with projects that have substantial preliminary data and the potential to significantly impact the field, to be truly transformative. The first of these awards went to Lori L. Isom, PhD and Jack M. Parent, MD of the University of Michigan in collaboration with Scott Baraban, PhD of the University of California San Francisco to investigate a novel therapeutic approach involving transplantation of a healthy progenitor cell from a region of the brain called the medial ganglionic eminence (MGE) into the brain of a rabbit model of Dravet syndrome. This technique has been effectively disease modifying in other animal models of epilepsy, and this will be the first time it is being tested in a Dravet animal model.
The remaining $975,000 of 2023 funding was directed to six additional grants that explore topics related to Dravet syndrome including dysfunction in neuronal communication, characterization of novel animal models, cardiac function, measurement of clinical outcomes, and sleep.
This year JAM for Dravet and Marlins for Mason are partnering with DSF to support funding for some of these projects. JAM (Julian’s Awareness Movement) for Dravet was inspired by Julian Chang, who was diagnosed with Dravet syndrome at one year old. His parents, Daniel and Deb, established the foundation to help accelerate cutting-edge pathways to a cure, raise awareness, and foster a robust community of support for families affected by Dravet syndrome. JAM for Dravet has also co-funded grants with DSF in 2021 and 2022. Marlins for Mason is an annual marlin release tournament held for the first time in 2023 in honor of Mason Prather, a 5-year-old with Dravet syndrome. The Prather Family organized this fundraising event with the goal to help find a cure and raise awareness for Dravet syndrome. DSF appreciates the important contributions from JAM for Dravet and Marlins for Mason to advancing research efforts for Dravet syndrome.
Read on to learn more about this year’s exciting projects and explore more about DSF funded grants here.
2023 DSF Grant Awards:
1. “Generating a shareable clinico-genomic data resource for Dravet syndrome”
Ingo Helbig, MD
Ethan M. Goldberg, MD, PhD
The Children’s Hospital of Philadelphia
Special 2023 RFA- $1,000,000 over 3 years
Funded with support from JAM for Dravet
Grant Summary: Individuals with Dravet syndrome can have different disease courses, and there are important differences in how seizure and development differences affect them over time. For example, some individuals have longer periods of seizure freedom, while other individuals have frequent seizures. Some individuals with Dravet syndrome have severe developmental differences and autism, while other individuals have typical or near-typical development. Even though the reasons for these differences have been discussed in the research field for the last decades, the underlying causes are not known. Identifying these causes may be helpful in providing accurate prognosis and developing new treatments by understanding the mechanisms. For many conditions, additional genetic factors are known to “modify” the main condition. Accordingly, it is reasonable to suspect the same role of “genetic modifiers” in Dravet syndrome, hopefully explaining some of the differences we see in individuals with Dravet syndrome. For this grant, we have tried to understand what would make a genomic dataset in Dravet Syndrome particularly meaningful. We suggest generating broad genetic data with whole genome sequencing (WGS) on 500 individuals with Dravet syndrome rather than limited genetic data. This is important, as all types of genetic analyses can be performed on this dataset. These genetic analyses will be paired with clinical data. Our advantage is that we have pioneered novel methods on how clinical information can be transformed to a format that can be used for computational analysis. Finally, we want to build this project for data sharing – all biosample data, genomic data, and clinical data will be shared within the Dravet Syndrome Community.
We have three aims for our project. First, we will use the infrastructure of our DSF-recognized Dravet Syndrome Comprehensive Care Center to enroll 500 individuals with Dravet syndrome in our research protocol. We will also gather information from 50 deceased individuals where DNA samples are available, either from research studies or diagnostic labs. We will translate the clinical data into a de-identified format for data sharing and analysis. Finally, we will use the so-called CAVATICA platform for data sharing, a tool that is supported by the NIH for data sharing. Our second aim is to use this dataset of genomic and clinical information to assess how different types of genetic variation on 25 clinical features that we derive from the medical records. This analysis will answer the question of how different types of genetic changes affect outcomes, such as seizure frequency or developmental milestones. As our third aim, we aim to build a clinic where we can share research data with our study participants, but also obtain additional clinical information that will add to our growing research dataset. In summary, we suggest a three-year research project to build a dataset for Dravet syndrome that consists of whole genome data and clinical data. This dataset will make it possible to ask questions on how genomic factors influence Dravet syndrome, which can identify strategies for improved treatment. We will take advantage of recent developments in data privacy to make sure that data sharing is meaningful, but also safe.
2. “Therapeutic benefit of MGE progenitor cell transplantation in a rabbit model of Dravet syndrome”
Lori L. Isom, PhD
Jack Parent, MD
University of Michigan
Scott Baraban, PhD
University of California San Francisco
Transformational Science Grant- $500,000 over 3 years
Funded with support from Marlins for Mason
Grant Summary: Dravet syndrome (DS) is a devastating developmental and epileptic encephalopathy that impacts approximately 1 in 16,000 individuals and places significant burdens on their families and caregivers. Importantly, DS is more than seizures. Its complex clinical presentation includes intellectual disability, developmental delays, movement and balance issues, language and speech disturbances, growth defects, sleep abnormalities, chronic infections, disruptions of the autonomic nervous system, and mood disorders. While all patients with epilepsy are at risk for SUDEP, DS patients have the highest risk, of up to 20%. Despite recent advances in small molecule drug discovery, the majority of DS patients remain intractable. Even if seizures can be controlled, small molecule drugs do not address the non-seizure phenotypes of DS, which are equally devastating to a patient’s quality of life. Clearly, it is essential that we address the underlying genetic cause of DS, which is for most patients, haploinsufficiency of SCN1A. A gene-modifying antisense oligonucleotide therapeutic agent to restore SCN1A expression is currently in clinical trials and viral-delivered gene replacement/enhancement strategies are under development. Here, we propose 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, rabbits, which are larger vertebrates, are more similar to humans than mice and have been successfully utilized to model human diseases, including Alzheimer’s disease. Here we propose to leverage the combined expertise and experience of the Baraban (in MGE transplantation) and Isom (in SCN1A models including transgenic rabbits) laboratories to develop a proof-of-principle disease-modifying cell transplantation-based therapy for DS. The results of this large animal work will strengthen the preclinical foundation for future cell transplantation therapeutic strategies in DS patients.
3. “Abnormal ectopic action potentials in PV-INs: A novel pathophysiological mechanism in Dravet syndrome”
Brian Theyel, MD, PhD
Research Grant- $250,000 over 2 years
Grant Summary: Dravet syndrome, which is caused by a mutation in the SCN1A gene, is a debilitating illness that emerges during the first year of life. It causes seizures, setbacks during development, speech and language problems, and balance and walking issues. The scientific understanding of how the SCN1A gene changes brain activity is rapidly evolving. Each step brings us closer to discovering new medications for this illness, which often does not improve with current treatment options. Our work will explore whether a brain cell that is integrally important in Dravet syndrome symptomatology has disruptions that lead to specific malfunctions. In the course of this work, we aim 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.
4. “Extended monitoring for cardiac arrhythmias in Dravet syndrome”
Mary Connolly, MB, BCh, FRCPC(C), FRCP(I), FRCP(Edin)
Shubhayan Sanatani, MD, FRCPC
The University of British Columbia
Clinical Research Grant- $250,000 over 2 years
Grant Summary: Dravet syndrome (DS) is a rare serious condition associated with early onset of seizures that typically do not respond to anti-seizure medications. Development and learning are affected in most patients. Individuals with DS have a higher chance of dying compared to those with other forms of seizures, and one common cause of this is sudden unexpected death in epilepsy (SUDEP) which occurs in 15-20% of individuals and is a great source of worry for all who care for individuals with DS. It is not fully understood how SUDEP occurs in DS, but seizures can cause rapid or very slow heart rates or rarely the heart may stop beating for a period of time. In a mouse model of DS, seizures affected the part of the brain that controls the heart and breathing and this suggests that abnormal heart rhythms triggered by seizures could be a major factor in causing SUDEP. In this study, we will place a heart monitor under the skin in 20 individuals with DS to measure their heart rhythms during seizures over a period of two years or longer. We will analyze information obtained from these monitors and seizures diaries to identify any serious abnormal heart rhythms that occur during seizures. This study aims to help us better understand how seizures affect the heart and if they can lead to life threatening heart rhythms. This knowledge could help lead to ways to prevent SUDEP in people with DS.
5. “DS-TIME: a multi-assessment approach to uncover the underlying mechanisms of sleep disturbances in children with Dravet syndrome”
Cristina R. Reschke, BPharm, MSc, PhD
RCSI University of Medicine and Health Sciences
Clinical Research Grant- $250,000 over 2 years
Grant Summary: Dravet syndrome (DS) is a very difficult to treat epilepsy syndrome characterized by seizures that start in the first years of life. However, a number of other symptoms are extremely relevant due to an expressive negative impact on the quality of life of DS children and their families. Among these, most caregivers report concerns about sleep problems and highlight the urgent need for a better diagnosis and management of severe sleep disorders in DS children. Despite there is some scientific evidence linking sleep disturbances to a disruption of the circadian system, the underlying mechanisms of sleep disturbances in DS children are poorly characterized. The sleep is mainly regulated by our body’s rhythms, named as circadian rhythms. The circadian system determines the 24-hour cycles in body changes, which include the regulation of sleep patterns, hormones, body temperature, and brain waves. These biological rhythms are driven by a master clock in the brain, called the suprachiasmatic nucleus, which is responsible for regulating the release of a neuro hormone called melatonin. Importantly, melatonin exerts an essential role in regulating the sleep-wake cycles in response to people’s exposure to environmental light or dark. Studies have shown that abnormalities in the circadian control of the secretion of melatonin may represent an important role in sleep disorders, however, the circadian cycle pattern remains unknown in DS children. Furthermore, the precise molecular mechanisms of sleep disturbances in DS children are also poorly understood and there are no tools to predict the risk of developing severe sleep problems. In this project, we will primarily focus on characterising sleep and circadian patterns in DS children and their families (siblings and caregivers), using multiple clinical and molecular assessments involving questionnaires, the use of a long-term actigraph device and multiple saliva collections. After, we will use several computational tools to identify and classify the severity of their sleep disturbances. Finally, we will link the clinical findings with the molecular findings to identify possible causes related to severe sleep disorders. The results obtained from this study will not only improve the understanding of sleep disorders in children with DS and its impact on their families but will also lay a crucial foundation for the future development of early diagnostic tools aimed at reducing these sleep disturbances in DS children.
6. “Mechanistic investigation in a novel mouse model of early-onset SCN1A-related disorders”
Sophie Hill, PhD
Mentor: Ethan M. Goldberg, MD, PhD
The Children’s Hospital of Philadelphia
Postdoctoral Fellowship- $75,000 for 1 year
Grant Summary: 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 cause 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. We have generated the first mouse expressing a patient-derived mutation associated with this severe early-onset condition. In this fellowship, we will evaluate the novel mouse for neurological abnormalities, including seizures and movement disorders. Additionally, we will investigate the electrical properties of neurons in mutant brain. Our 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.
7. “Establishing the role of the noradrenergic network during seizures in Dravet syndrome”
Meiling Zhao, PhD
Mentor: Joanna Mattis, MD, PhD
Co-Mentor: Jack Parent, MD
University of Michigan
Postdoctoral Fellowship- $75,000 for 1 year
Grant Summary: Individuals with Dravet syndrome 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 therapeutic strategies. 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 coordinate brain-wide states, such as reward and attention; I hypothesize that it also plays a critical role in seizures in Dravet syndrome. I will use a mouse model of Dravet syndrome, further engineered to enable access to noradrenergic neurons, to (1) determine the activity of these neurons during seizures and (2) test whether their activation curtails seizures.
8. “Increasing clinical trial readiness in Dravet syndrome- Creation and pilot of Dravet-specific clinical outcome measures”
Megan Abbott, MD
Mentors: Kelly Knupp, MD and Scott Demarest, MD
University of Colorado Denver
Clinician-Researcher Award- $75,000 for 1 year
Grant Summary: Dravet syndrome (DS) is the most common genetic cause of Developmental and Epileptic Encephalopathy (DEE), yet there are no FDA approved disease modifying treatments. Current precision therapeutic clinical trials for DS utilize seizure frequency as the primary outcome measure. Utilizing seizure frequency 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 test the hypothesis that valid and feasible outcome measures can be designed specifically for DS that represent the full range of the phenotype beyond seizure frequency. The creation of the Dravet Syndrome clinical severity assessment-clinician and caregiver (DS-CSA) will be a crucial step towards disease modifying clinical trial readiness in DS.