DSF was established with a primary mission focused on advancing research. One way in which DSF works toward accomplishing this mission is through our yearly grant funding cycle, which has directed over $5.6 million to Dravet-focused research since 2009. This year we announced at our annual Research Roundtable that we are funding an additional 5 research grants, totaling $705,000, and bringing our total research funding to over $6.4 million. Importantly, this year three of our funded grant projects are focused on Sudden Unexpected Death in Epilepsy (SUDEP), a major risk factor for early mortality in patients with Dravet syndrome. These projects will explore cardiac function in patients with Dravet syndrome, the impacts of carbon monoxide on symptom presentation and survival in a mouse model of Dravet syndrome, and how odorants activate specific brain regions and impact risk of SUDEP in mice. Another of the funded research grants will use a unique Dravet mouse model to explore how correction of the SCN1A mutation in different cell types in the brain impacts symptoms, a study which will be informative to the development of future genetic therapies for patients. Additionally, we are funding a grant to explore how a specific region of the brain, the cerebellum, may contribute to non-seizure symptoms of Dravet syndrome such as gait, behavior, and cognition. DSF is proud of all that has been accomplished from our past funding efforts and we are excited to see these projects progress and advance our knowledge, and ultimately treatment, of Dravet syndrome.
This year, another organization, JAM for Dravet, has stepped forward once again to co-fund two of these projects with DSF. 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. DSF appreciates their important contribution to advancing research efforts for Dravet syndrome
Read on to learn more about the projects and researchers DSF is funding this year.
David Auerbach, PhD – The Research Foundation for SUNY/Upstate Medical University
“Genetic Substrates and Physiological Triggers for Autonomic and Cardiac Abnormalities in Dravet Syndrome”
Clinical Research Grant – 2 years, $150,000
**Co-funded with JAM for Dravet
Dr. David Auerbach is an Assistant Professor of Pharmacology at SUNY Upstate Medical University. He has shown that it is important to take a multi-system approach to studying electrical diseases of both the brain and heart. He is actively investigating the prevalence, risk factors, and mechanisms for the multi-system cascade of events that lead to Sudden Unexpected Death in Epilepsy Patients (SUDEP).
Grant Summary: Patients with Dravet syndrome (DS) are at a high risk of sudden death. The cause of death is often unknown, and is termed Sudden Unexpected Death in Epilepsy (SUDEP). Parents plea that their child might be alive if we could identify predictive markers for SUDEP. We need to look outside the brain to reduce the risk of sudden death. Using cellular and animal models, I demonstrated that DS mutations result in electrical disturbances in the heart, and cardiac arrhythmias preceded SUDEP. While our cellular results identified a DS patient with electrocardiographic (ECG) abnormalities, the translational relevance of these results remains unknown. We will perform detailed ECG analysis in two severe forms of epilepsy (DS & Lennox-Gastaut Syndrome, LGS). We will perform detailed ECG analytics during specific non-seizure physiological states and investigate the temporal evolution of these measures leading up to and following a seizure. As cardiac arrhythmias provide one possible cause for SUDEP, we will demonstrate the prevalence and conditions for cardiac electrical abnormalities in DS and LGS, which will foster the future development and validation of ECG markers for cardiac-mediated SUDEP risk in DS patients.
Ashwini Sri Hari, PhD – University of Utah
“Evaluating the effects of sub-chronic exposure to sub-clinical levels of CO on Dravet etiology and associated SUDEP risk”
Postdoctoral Fellowship – 1 year, $75,000
Dr. Ashwini Sri Hari earned her bachelor’s and master’s degrees in Biotechnology from India. She pursued her PhD in Toxicology with a special focus on epilepsy and seizure disorders under the mentorship of Dr. Manisha Patel at the University of Colorado – Anschutz Medical Campus. Ashwini joined the esteemed NINDS Anticonvulsant Drug Development (ADD) Program at the University of Utah and is currently under the prestigious mentorship of Drs. Karen Wilcox and Cameron Metcalf. Here, she has the opportunity to continue working on screening drug compounds in a mouse model of DS that harbors a clinically relevant missense, loss of function mutation in the SCN1A voltage-gated sodium channel gene. Additionally, her research focuses on delineating the molecular mechanisms that cause Sudden Unexpected Death in Epilepsy (SUDEP) and how environmental factors may impact risk.
Grant Summary: 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. The question of whether and how CO exposure exacerbates pathomechanisms in DS patients and their associated SUDEP risk is unknown. The experiments proposed in this proposal aim to address these questions.
Gaia Colasante, PhD – Universita Vita-Salute San Raffaele
“Reactivating Scn1a gene in different interneuron subtypes to dissect their contribution to Dravet syndrome phenotype”
Research Grant – 2 years, $150,000
Dr. Gaia Colasante earned her degree in Biotechnology at University of Milan and her PhD in Neuroscience and Molecular Medicine at University Vita-Salute San Raffaele working in Dr Vania Broccoli Lab. She was interested in forebrain development and in particular she dissected the contribution of the transcription factor Arx in those processes. This interest brought her at Children’s Hospital of Philadelphia in the laboratory of Dr. Jeffrey Golden, where she continued to study the role of Arx transcription factor in GABAergic interneuron migration exploiting time-lapse imaging technique. When back to San Raffaele Hospital, she turned to cell reprogramming, defining a cocktail of transcription factors able to convert fibroblasts and pluripotent stem cells s into GABAergic interneurons as a source of cells for cell-replacement therapies in epilepsy. More recently, she exploited activatory CRISPR/dCas9 strategy to up-regulate therapeutic genes in genetic and non-genetic forms of epilepsy. She is now project leader at San Raffaele Hospital and she manages a small team committed to the development of gene therapy for the treatment of Dravet syndrome and other neurodevelopmental disorders.
Grant Summary: Dravet syndrome (DS) is a devastating epileptic syndrome with associated relevant behavioral alterations. Heterozygous mutations in Scn1a gene account for the disease and its gene product, the sodium channel Nav1.1, is relevant for neuronal activity. For many years this channel has been considered essential only for the activity of GABAergic interneurons, that are the main source of inhibition in the brain. However, it is now that it was just a simplicist view of the pathology. In fact, in DS mouse models this dysfunction seems to be only the trigger of the disease while more complex mechanisms underlie its progression. The present project aims to shed light on those mechanisms, with a particular interest in the understanding of the contribution of the different GABAergic interneuron subtypes to the pathogenesis. We will employ a novel mouse model we recently generated, a reversible mouse model of DS. Those mice are born with the disease, but exploiting a genetic strategy, we can restore the exact gene dosage selectively in the desired neuronal population. In this set of experiments, we will restore Nav1.1 normal level in interneuron subtypes, and we will investigate the effect on the main aspects of Dravet phenotype, including SUDEP, seizures and behavioral alterations. We will also analyze how neuronal activity at circuit level changes upon selective Scn1a gene reactivation in those neuronal populations. We believe that the results of this study will advance the knowledge in the field and, most importantly, will provide information relevant for the setting of more efficient gene therapy strategies.
Mackenzie Howard, PhD – The University of Texas at Austin
“Cerebellar deficits as mechanisms for motor, cognitive, and social dysfunction in Dravet syndrome”
Research Grant – 2 years, $165,000
Dr. MacKenzie Howard was a burned-out cellular neurophysiologist who found new inspiration and motivation after shifting into the field of translational epilepsy research when he joined Dr. Scott Baraban’s lab for a second postdoc. Upon starting his own lab at Dell Medical School / University of Texas at Austin, he focused his research on studying basic mechanisms of Dravet syndrome using mouse models. His primary interest is in how changes in neural information processing at the cellular level cause the ongoing cognitive, affective, and motor comorbidities that persist between seizures in Dravet syndrome.
Grant Summary: In addition to frequent and severe seizures, most people with Dravet syndrome also suffer life-altering difficulties (“comorbidities”) with coordinated movement/muscle control, autism-associated behaviors, and learning and memory that continue even when their seizures are medically controlled. The cerebellum is a brain region known to be involved in movement, cognition/memory, and social behavior, but is understudied in Dravet syndrome and epilepsy in general. Our lab has new preliminary data showing that the physiology of a certain type of neurons in the cerebellum, Purkinje cells, are hypo-active in a mouse model of Dravet syndrome. Similar hypoactivity of this cell type causes movement disorders and autism in other neurological diseases. Previously, the link between Purkinje cell dysfunction and the neurological deficits of Dravet syndrome has been difficult to study due to the very early age at which Dravet syndrome mice die. However, we have bred a new mouse line in which only cerebellar Purkinje cells have the Dravet syndrome mutation. These mice survive into adulthood, begin to show changes in movement and other behaviors. We will use these mice as a new tool to study Purkinje cell function and how cerebellar dysfunction causes the changes in motor control, social behavior, and learning difficulties seen in Dravet syndrome. We will take a team approach to this problem: Dr. Howard’s lab specializes in cell physiology in Dravet syndrome and will examine Purkinje cell properties; our collaborators in Dr. Brumback’s lab specialize in autism spectrum disorder and will examine social behavior in these mice; Dr. Nishiyama’s lab specializes in the function of the cerebellum and will examine learning and memory in this neural circuit.
William Nobis, MD, PhD – Vanderbilt University
“Effect of odorant on mortality and extended amygdala activation in Dravet syndrome”
Research Grant – 2 years, $165,000
**Co-funded with JAM for Dravet
Dr. William Nobis is an Assistant Professor at Vanderbilt University Medical Center. He completed the Medical Scientist Training Program at Vanderbilt University in 2011 where he earned both his M.D. and a Ph.D. in Neuroscience followed by Neurology and Epilepsy training at Northwestern University in Chicago, where he served as chief resident in 2015. Dr. Nobis’ research focuses on sudden unexpected death in epilepsy (SUDEP), in particular electrophysiological and targeted functional anatomical evaluation of extended amygdalar circuits and its relation to seizures and respiratory control in genetic epilepsies such as Dravet syndrome.
Grant Summary: Dravet syndrome (DS) is associated with a high epilepsy-related mortality, including an increased risk of sudden unexpected death in epilepsy (SUDEP). Controlling seizures can decrease the risk of SUDEP, but seizures in DS are often refractory and anti-seizure medications have unwanted side effects, outlining the need for a benign treatment option to modify mortality risk. Odor therapy, or aromatherapy, has been used for a therapy for stress, depression and neurologic disease including a historical background in treating seizures. The olfactory system is unique in that it is a sensory organ that does not send its information to the thalamus, rather it has direct connections to olfactory areas of the brain but also to areas that are more evolutionarily and classically involved in stress, fear, threat detection and social functioning. These include areas of the brain known collectively as the extended amygdala. More recent work by myself and others have determined that there is a role of these amygdalar circuits in control of respirations and potentially seizure related breathing dysfunction. Odorants that have a direct input to amygdalar circuits have the potential to modulate these circuits and may provide a non-invasive, well-tolerated means to decrease seizure-related death by preventing activation of these regions and altering seizure-related breathing dysfunction. Our hypothesis is that 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. Exciting preliminary data using a mouse model of DS suggests that mortality is significantly reduced by chronic exposure to this odor, our goal is to build on this data to better explore the effects of odor exposure on mortality, seizure frequency and neuropsychiatric comorbidities. This work would provide scientific rationale for the use of odor therapy to manage symptoms of epilepsy and DS, this would be immediately clinically impactful and could readily be evaluated in clinical setting to prove efficacy in human patients.