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Pierre Drapeau, Ph.D and Eric Samarut,Ph.D, MBA
– Research Center of the University of Montreal Hospital Center, Quebec
-2016

Eric Samarut

In partnership with the Rare Disease Models and Mechanisms Network (RDMM), Drs. Pierre Drapeau and Éric Samarut were awarded $12 5000 by dravetCanada for their project using the zebrafish model to characterize the phenotype of novel Dravet Syndrome (DS)-causing genes and screen for potent small molecules that could rescue their DS-like condition in two novel candidate genes, GABRA1 and CHD2. For GABRA1, they generated a knockout in zebrafish leading to generalized epilepsy. This is the first non-chemically inducible epilepsy model with evident generalized seizures as well as SUDEP (Sudden Unexpected Death in EPilepsy). Through whole transcriptome analysis and immunolabelling they found that this is the first in vivo evidence that GABA receptor-mediated generalized epilepsy is, at least in part, due to neurodevelopmental defects. They demonstrated that the zebrafish line they generated is a powerful tool for further drug-screen, paving the way for the discovery of new therapeutics for a broad range of epilepsies. Their work is pioneering in providing in vivo data showing that idiopathic epilepsies should be considered as developmental diseases rather than chronic neurological hyperexcitation. This is of prime importance for the deployment of further therapeutic strategies that would restore the developmental defects observed in the epileptic brain rather than simply attenuating the seizures.

Danielle Andrade, MD, MSc, FRCPC
– Krembil Neuroscience Epilepsy Genetics Research Program, University Health Network, Toronto, Ontario
– 2016

Dr. Danielle Andrade and her team were awarded $35 000 for their project studying “Long-term outcomes in Dravet Syndrome”. The first objective of their work is to investigate the progression of cognitive and behavioural changes along the course of Dravet syndrome (DS), especially after adolescence. The specific hypothesis behind the proposed research is that there is neurocognitive and behavioural decline as patients age. So far most research assessed the cognitive status in paediatric Dravet patients. Therefore, there is scant information about how subjects diagnosed with DS evolve into adulthood, from the neuropsychological standpoint. The second objective is to evaluate how adults with Dravet syndrome respond to medications traditionally used to treat children with DS. So far most studies evaluating the treatments for Dravet syndrome have been done in children. However, in our experience, adults with DS do not react in the same manner to the medications typically used for children with DS. Furthermore, the adults with DS have a different seizure severity and have new motor problems. So far there are no studies exploring how adults with DS should be treated and the treating neurologist will typically follow the treatment suggested for children. This may or may not be appropriate and it is therefore important to understand how adults with DS respond to medications.

Peter Ruben, Ph.D – Simon Fraser University, British Columbia
– 2016

Dr. Peter Ruben

Dr. Peter Ruben and his team were awarded $20 000 for their project studying “Triggers for Dravet-Associated Seizures”. The mechanisms causing temperature sensitivity in Dravet syndrome are not well understood. The overall goal is to understand the role that environmental triggers, such as temperature, play in seizure generation. The present aims are to elucidate whether altered sensitivity to febrile temperatures is intrinsic to all Dravet variant NaV1.1 channels, and – if so – how this may be expected to alter the firing patterns of individual neurons expressing these mutants. The specific aim of this present proposal is to extend our past and present findings to an in vivo model of Dravet febrile seizure generation.

Abby Collier, Ph.D – Faculty of Pharmaceutical Science, University of British Columbia – 2016

Dr. Abby Collier

Dr. Abbey Collier and her team were awarded $10 000 for their project titled ‘A Pharmacogenomic Study of Interactions Between SCN1A and UGT Variants Affecting Lamotrigine Efficacy and Toxicity in Children with Dravet’s Syndrome’. It is not well understood why lamotrigine worsens seizures in Dravet Syndrome and whether this might be due to drug toxicity by metabolism or by channel interactions. This project can define the developmental drug handling of lamotrigine (LTG) and interactions between disease etiology (SCN1A) and drug handling (UGT) that may be resolved by altered drug dosing. The advantage is that children are not exposed to potentially sub-therapeutic or toxic doses of drugs but human-specific data can be gained. The outcome from this research will be to provide evidence-based dosing guidelines (dosages, dose intervals) for expanded practice with LTG to better serve the Dravet community.

David Dyment, DPhil, MD, FRCPC
– CHEO Research Institute, University of Ottawa, Ontario
– 2017

Dr. Dave Dyment and his team were awarded $50 000 for their project entitled “A Comprehensive Approach to Drug Repurposing to Reduce Seizures in Dravet Syndrome”. Their plan is to expand the potential therapeutic options for those living with Dravet Syndrome. To do so, they will optimize a pipeline to re-purpose drugs that includes in vitro and in vivo models. They have generated a mouse model of Dravet Syndrome in collaboration with The Centre for Phenogenomics (Toronto, Canada). The mouse model incorporates a substitution based on the genotype of an individual with Dravet syndrome living in Canada. In addition to the use of this novel mouse model system, they will also be creating induced neurons from the fibroblasts of this patient and other individuals with Dravet Syndrome. The induced neurons can be cultured to form a dissociated network of neurons that may better reflect the complexity seen in the central nervous system. These innovative models will then be used to screen a library of 250 CNS-specific drugs in a novel assay system known as multichannel electrode arrays (MEAs). Any candidate drugs identified by the assay can then also be tested, in vivo, in the mice, to assess for seizure reduction. The work they propose for this grant is therefore a part of their translational research program to provide tailored treatment options to those with Dravet Syndrome.

Elizabeth Donner, MD, MSc, FRCPC
– Comprehensive Epilepsy Program, The Hospital for Sick Children, Toronto, Ontario
-2015

Dr. Elizabeth Donner and her team were awarded $20 000 for their project entitled “A Case-Control Study of SUDEP in Dravet Spectrum Disorders (DSD)”. Their first objective is to create a network of collaborators to identify Dravet Spectrum Disorders SUDEP cases and Dravet Spectrum Disorders living controls. Collaborations will be established with DSD advocacy groups and clinical experts working in DSD. Working with the North American SUDEP Registry, they will assemble collaborators from Canada, the US, Europe, Asia and Australia to optimize case ascertainment of SUDEP in Dravet Syndrome. Several collaborations are already established. Each participating centre will obtain institutional research ethics board approval. Their second objective is to determine the frequency of recognized and novel risk factors for SUDEP in DSD. A case-control cohort will be assembled.

David Hampson, BSc, MSc, PhD
– University of Toronto, Ontario
-2015, 2016, 2017

Dr. David R. Hampson

Dr. David Hampson and his team were awarded in 2015 $20 000 for their project entitled “A Pilot Study of Gene Therapy in a Mouse Model of Dravet Syndrome” Using highly customized viral vectors to rescue abnormal CNS biochemistry and behaviour in a mouse model of Dravet Syndrome, they hypothesize that viral vector-mediated gene therapy represents a viable approach to treating CNS genetic disorders such as Dravet Syndrome. A huge advantage of gene therapy is that a single administration of the vector translates into long-term transgene expression (vector-mediated protein synthesis) in the CNS, thus potentially inducing comprehensive and lasting correction of the disorder. They will examine the application of viral vector therapy for correcting abnormal inhibitory neurotransmission in Dravet mice where the NaV1.1 sodium channel is mutated. The seizures, and possibly other symptoms of Dravet Syndrome, are thought to be largely induced by impaired neurotransmission in GABA-containing inhibitory neurons due to the defective NaV1.1 channels in these cells. Therefore, a specific objective is to boost the effectiveness of these neurons by selectively expressing wild-type NaV1.1 channels in GABA neurons. Success in selectively targeting vector expression to inhibitory neurons could have additional positive spin-offs by demonstrating proof-of-principle, and thereby potentially extending applicability of this strategy to other neurological/psychiatric disorders seeking to modify GABAergic neurotransmission in the brain.

In 2016 and 2017, Dr. Hampson was awarded $5,000 each year as “continuing funding” to secure a $600 000 grant through CIHR (Canadian Institutes for Health Research) to further his study into “Gene Therapy in a Mouse Model of Dravet Syndrome”.

Toronto General & Western Hospital Foundation, Ontario
-2014

Doctors associated with the Toronto General & Western Hospital Foundation were awarded $15 000 for a project entitled “High CBD Low THC Cannabis Sativa Extract from Genetically Selected Cannabis Sativa as Add-on Treatment for Drug Resistant Epilepsies”. Funding provided by dravetCanada was used to prepare the way for a group of studies being coordinated under the EpLink team – The Epilepsy Research Program of the Ontario Brain Institute.