Jeffrey Calhoun, PhD – Northwestern University
$50,000 Postdoctoral Fellowship (1 year project)
Target validation of thalamic T-type calcium channels in a mouse model of Dravet syndrome
Modifier genes influence the severity of epilepsy in Dravet Syndrome and other genetic epilepsies. These epilepsy modifier genes may represent targets for the design of novel therapeutic interventions. We previously identified a modifier gene, Cacna1g, that influences seizure susceptibility in a mouse model of Dravet Syndrome. One goal of this fellowship is to determine whether Cacna1g and related gene Cacna1h are potential molecular targets for therapy using genetic and pharmacological tools in a mouse model of Dravet Syndrome. The other goal of this fellowship is to map the neuronal circuits activated during seizure initiation and propagation in a mouse model of Dravet Syndrome.
Aliesha Griffin, PhD – University of California, San Francisco
$50,000 Postdoctoral Fellowship (1 year project)
Optimization of clemizole as a novel treatment for Dravet syndrome
There is a significant need to develop new therapeutic treatments for Dravet syndrome patients as many children suffer persistent drug resistant seizures. Like Dravet syndrome patients, zebrafish with a mutation in SCN1A gene also have seizure-like behaviors.The antihistamine clemizole was able to significantly reduce these seizure-like episodes. However, antihistamines are typically not recommended for Dravet syndrome patients. By modifying the chemical structure of clemizole we can remove its antihistamine activity and improve its antiepileptic properties. These new compounds will be tested for antiepileptic activity using our Dravet syndrome zebrafish model. I anticipate these new versions of clemizole will provide a platform for developing a new treatment for Dravet syndrome.
Evangelos Kiskinis, PhD – Northwestern University
$165,000 – Research Grant (2 years)
Using patient specific iPSC-derived neurons to identify molecular biomarkers of drug treatment responsiveness in Dravet syndrome
Dravet syndrome remains particularly difficult to treat, with one third of all patients failing to respond to any of the currently available anti-seizure medication. In all cases it is hard to predict how a patient will respond to a drug and clinicians often have to resolve to a trail-and-error approach that can have devastating repercussions for patients and their families. Using Dravet patient-specific stem cells we aim to carefully examine brain cells from patients that have shown good seizure control after drug treatment as well as patients that have been completely refractory to drug treatment. By studying the electrical patterns, the molecular properties and the responses to drugs of these brain cells grown in a dish we aim to: a) understand what makes brain cells respond well to drugs, and b) determine whether we can predict what drug would work best for each patient simply by studying their cells. If successful, our approach will have a major impact in how we diagnose and treat Dravet as well as patients suffering with other kinds of epilepsies.
Dennis Lal, PhD – The Broad Institute
$150,000 – Research Grant (2 years)
A Novel System to evaluate SCN1A Pathogenicity
Predicting the consequences of mutations identified in clinical screens is far from easy. This is particularly true for genes like SCN1A where variants can be neutral or lead to a wide spectrum of disorders. We will develop novel methods to computationally distinguish pathogenic from benign variants in SCN1A and related genes in patients with Dravet syndrome (DS) and related epilepsies. In our analyses, we will incorporate chemical, biological and a wide range of additional information of mutations in DS-genes to identify differences between patients and controls. The developed methods and findings will be available online to aid variant prediction and drug development.
Ruth Westenbroek, PhD – University of Washington
$164,000 – Research Grant (2 years)
Understanding the mechanisms and efficacy of cannabidiol (CBD).
Dravet Syndrome (DS) is one of the most severe childhood neuropsychiatric diseases, with symptoms including febrile seizures and intractable epilepsy, developmental delay, ataxia, sleep disorder, autistic-like behaviors, frequent premature death, and profound cognitive deficit. Life-threatening pediatric epilepsies such as DS are unresponsive to standard therapies. Clinical and preclinical results suggest that cannabidiol (CBD), a non-psychoactive derivative of marijuana, may have novel antiepileptic effects. We will test the hypothesis that CBD attenuates or completely eliminates thermally evoked seizures, spontaneous seizures and/or sudden unexpected deaths using our mouse model of DS. Mice with heterozygous loss-of-function mutations in the Scn1a gene encoding Nav1.1 voltage-gated sodium channels have been shown to be an exact phenocopy of the human DS disease and provide us a unique opportunity to understand the mechanism of action of CBD. Determination of the underlying mechanisms will not only provide a solid basis for the development of a new class of anti-epileptic medicines to benefit pediatric epilepsies but also help the field to better understand key physiological processes that can be targeted to control intractable seizures. The mechanisms investigated here will help guide the next stages of this research in our attempt to discover potentially effective drug combinations for intractable epilepsies.
Orrin Devinsky, MD – NYU Comprehensive Epilepsy Center and the Saint Barnabas Institute of Neurology and Neurosurgery.
$50,000 – Ataluren Trial
PTC Therapeutics, the Dravet Syndrome Foundation, and FACES are sponsoring a trial of Ataluren to treat children with treatment-resistant epilepsy associated with Dravet Syndrome or CDKL5 due to stop codon (nonsense) mutations. These are DNA changes in which one DNA nucleotide is substituted for another one and instead of the three letter DNA sequence coding for an amino acid, it codes for a message to prematurely stop the amino acid chain and prematurely terminate the SCN1A or CDKL5 protein, resulting in a roughly 50% reduction in the amount of functional protein since these partial proteins are typically metabolized rapidly by nerve cells. Eight children with Dravet Syndrome and eight children with CDKL5 will be enrolled in this double-blind placebo controlled crossover study.
Stephanie Makinson, PhD – The Gladstone Institutes
DSF & AES Early Career Research Partnership – $45,000 (1 year project)
The therapeutic potential of the thalamus in Dravet syndrome
Dravet syndrome (DS) is a severe childhood epilepsy for which there is no cure and current treatments often cause major side effects. Most patients with DS have a mutation in the gene, SCN1A, which changes the function of the SCN1A protein and causes seizures. While inhibitory cells in the thalamus express high levels of SCN1A, we only recently learned that this region of the brain is abnormal in Dravet syndrome. With a well-established mouse model of DS that expresses the mutated human Scn1a gene, we showed, for the first time, that the thalamus is pathological and can generate epileptic activity in Dravet syndrome mice. We then manipulated the activity of the inhibitory cells in the thalamus by delivering light specifically to these cells, which interrupted ongoing seizures in freely behaving DS mice. In the proposed project, our goal is to use novel optical approaches to either disrupt or order the activity of inhibitory cells in the thalamus to determine if they cause seizures in Dravet syndrome mice. This work will serve as a proof-of-concept that we could target the thalamus to treat, and potentially cure, Dravet syndrome.