PAST RESEARCH ROUNDTABLES
2016 7th Annual DSF Research Roundtable
by Nicole Villas, DSF Board President
Dravet Syndrome Foundation was proud to host their 7th annual Research Roundtable prior to the American Epilepsy Society (AES) meeting in Houston, Texas, on December 1, 2016. Sponsored by GW Pharmaceuticals, Zogenix, Dr. and Mrs. Morton Sperling, Frank Kuchuris, an anonymous donor, and Xenon Pharmaceuticals, the Roundtable offered attendees a snapshot of the exciting research being conducted in Dravet syndrome. Experts in several fields presented updates on current and recently completed projects.
Dr. Jack Parent of the University of Michigan and Dr. Scott Baraban of the University of California at San Francisco moderated the evening, which began with Dr. Orrin Devinsky of NYU Langone Medical Center summarizing two current clinical trials. Epidiolex, a cannabidiol (CBD) extract manufactured by GW Pharmaceuticals, is currently in Phase 3 testing, while Ataluren, a potential read-through treatment for nonsense mutations, will be studied in a double-blind crossover trial partially funded by DSF. Dr. Biljana Djuvic, with the Gladstone Institute of Neurological Disease, then presented her work on tau reduction in a Dravet syndrome mouse model and the effects on early mortality, seizure frequency, and spatial learning. Dr. Alison Muir, 2015 DSF grant recipient with the University of Washington, summarized her project involving searching for the mutations responsible for Dravet syndrome in the 20% of the population that initially tests negative for SCN1A mutations.
After a short break, Dr. Yishan Sun of the Novartis Institutes for BioMedical Research outlined his manipulation of human induced pluripotent stem cells (hiPSCs) through various differentiation methods to create specially labeled neurons. Dr. John Oakley, 2015 DSF grant recipient with the University of Washington, presented progress on his two-year study of time-selective activation of SCN1A mutations in a mouse model. The presentation portion concluded with Dr. Jennifer Wong of Emory University reviewing her work on Huperzine A, an acetylcholinesterase inhibitor often used in Alzheimer’s disease that was recently found to protect against seizures in a Dravet syndrome mouse model as described in Frontiers in Pharmacology.
Following the presentations, Dr. Baraban moderated a discussion about next steps for Dravet syndrome research, which sparked thoughtful conversation among those dedicated to finding better treatments and, ultimately, a cure for Dravet syndrome. DSF would like to express our sincere gratitude to the sponsors, moderators, speakers, discussion participants, and attendees at this year’s Research Roundtable, which sparked valuable discussion and brainstorming that continued throughout the weekend at the AES meeting.
2015 DSF Research Roundtable
by Nicole Villas, DSF Scientific Director
The Dravet Syndrome Foundation is proud to have hosted the sixth annual Research Roundtable, which brought together the scientists and medical professionals working toward a cure for Dravet syndrome, on December 3 in Philadelphia, Pennsylvania.
The presentations by previous DSF Research Grant recipients and others working on research in Dravet syndrome sparked an evening of questions, collaboration, and brainstorming as the scientists, geneticists, neurologists, and other professionals worked on possible next steps toward a cure. Discussions continued throughout the weekend during the annual AES Meeting, and DSF is grateful for the dedication of everyone who was present.
After a buffet dinner and welcome by DSF Board President Abby Hemani, Drs. Jack Parent (University of Michigan) and Scott Baraban (University of California at San Francisco) moderated the evening’s presentations, summarized below. Past DSF grant recipients are listed in bold:
Alfred L. George, Jr., MD, explained his study of the novel sodium channel modulator GS967 and its effect on a Dravet mouse model, including its effects on induced seizures and survival rate. His study was showcased in a poster presentation at AES, can be viewed here. Shinichi Hirose, MD, PhD, presented his work with patient-derived induced pluripotent stem cells, sharing how the cells grow and behave in a neuronal network. Ted Cummins, PhD, shared his findings on mutations in sodium ion channels 1.1 and 1.6, resurgent currents, and the hyperexcitable states produced. Gemma Carvill, BSc, PhD, presented her lab’s exciting study on the effects of mutations in CHD2, a chromatin modifier gene that affects DNA transcription and often results in epilepsy, suggesting it may be an activator for common epilepsy genes. MacKenzie Howard, PhD, explained his lab’s work with neuronal cell transplantation and their study of the migration and integration of both healthy cell transplants and, potentially, mutated transplants. An AES poster abstract with some of the transplantation information is found here. Michael Hammer, PhD, shared the results of his search for modifier genes in Dravet syndrome. By focusing on specific genotypes and outlying phenotypes, he was able to perform innovative statistical analysis on a small population to discern possible relationships between SCN1A and its potential modifiers.
We thank our sponsors for the evening: GW Pharmaceuticals, Zogenix, the Johnson Family Foundation, Dr. & Mrs. Morton Sperling, and an anonymous donor.
5th Annual Research Roundtable By Lori Isom, PhD
The fifth annual DSF Research Roundtable was held on December 4, 2014 in Seattle, WA. This gathering, held during the annual meeting of the American Epilepsy Society, and sponsored by GW Pharmaceuticals and Transgenomic, brought together researchers, geneticists, neurologists, parents, and other professionals with a strong interest in Dravet syndrome and related epilepsies. The purpose of this annual roundtable is to establish a research roadmap to guide DSF in funding research projects that address the critical challenges of this syndrome and to determine which projects will offer the most promising breakthroughs at the fastest pace. This strategy of prioritizing research needs by a consortium of experts allows DSF to facilitate the development and implementation of better treatment options.
DSF Board Member, Abby Hemani, welcomed guests and invited everyone to share in a wonderful networking dinner. Dr. Jack Parent of the University of Michigan and Dr. Scott Baraban of the University of California San Francisco moderated the scientific portion of the program. The agenda included presentations from current and previous DSF grant awardees as well as other experts in the Dravet syndrome field: Dr. Joseph Sullivan (Associate Professor of Neurology and Pediatrics and Director of the University of California San Francisco Pediatric Epilepsy Center) gave the audience an overview of Dravet syndrome. Dr. William A. Catterall (Professor and Chair of Pharmacology at the University of Washington), described his current research efforts to dissect phenotypes using cell type specific gene deletion in a SCN1A mouse model of Dravet syndrome. Dr. Yvonne Wu (Professor of Neurology and Pediatrics at University of California San Francisco and recipient of DSF funding) shared the results of her recent study on the population incidence of Dravet Syndrome. Dr. Sam Berkovic, from the University of Melbourne, then stepped in for Dr. Steven Petrou whose plane from Australia was canceled. Dr. Berkovic shared Dr. Petrou’s exciting preclinical assessment of a Nav1.1-targeted therapeutic for Dravet syndrome. Samantha Turner, a pediatric speech pathologist who is completing her PhD at the University of Melbourne, shared her results on speech and language difficulties in children with Dravet syndrome. Finally, Dr. Jokubas Ziburkus (Associate Professor of Biology and Biochemistry at the University of Houston and recipient of DSF funding) reported his results on purinergic control of neural circuit hyperexcitability, seizures, and co-morbidities in a SCN1A mouse model of Dravet syndrome.
For the fifth year in a row, the program was outstanding, providing not only new scientific information, but also invaluable opportunities for networking between academic and industry scientists, physicians, and advocacy organizations within the Dravet syndrome community.
4th ANNUAL DSF RESEARCH ROUNDTABLE
Lori O’Driscoll, DSF President, welcomed attendees to the meeting with a presentation of a moving video telling the story of Will Bubela, a 4 year old with Dravet syndrome, and his family. Dr. Jack Parent of the University of Michigan and Dr. Scott Baraban of the University of California San Francisco then moderated the scientific portion of the program. The agenda included presentations from current and previous DSF grant awardees, as well as other experts in the Dravet syndrome field: Dr. Linda Laux (2013 DSF grant awardee from Northwestern University) updated the audience on existing and new therapies for Dravet Syndrome. Dr. Ana Mingorance-Le Meur from DSF Spain described available research tools for the Dravet community. Dr. Jing-Qiong “Katty” Kang (2012 CURE/DSF awardee from Vanderbilt University) shared her recent results on the GABRG2 (Q390X) mouse model of Dravet syndrome. Dr. Miriam Meisler (University of Michigan) reported on the functional implications of novel mutations in SCN8A, encoding the sodium channel Nav1.6, in epileptic encephalopathy. Dr. Kazuhiro Yamakawa (RIKEN Brain Institute in Japan) summarized his recently published work in support of the Dravet syndrome interneuron hypothesis showing that SCN1A deletion in mouse parvalbumin-positive interneurons is sufficient to cause spontaneous epileptic seizures. Dr. Scott Baraban (2011 CURE/DSF awardee from the University of California San Francisco) presented his innovative work using a mutant scn1a zebrafish model to screen for novel therapeutics in Dravet Syndrome. Finally, Dr. Franke Kalume (University of Washington) presented a potential mechanism of SUDEP in the Scn1a+/- Dravet Syndrome mouse model that implicates changes in autonomic neuronal excitability.
For the fourth year in a row, the program was outstanding, providing not only new scientific information, but also invaluable opportunities for networking between academic and industry scientists, physicians, and parents of children with Dravet Syndrome.
2012 Research Roundtable By Michael Carey, MD
The 3rd annual DSF Research Roundtable attracted more than anticipated numbers of basic science researchers and physicians. Direct interaction between those doing research and those treating patients, in an attempt to refine and direct studies, is a powerful dynamic that the Research Roundtable provides. Several participants lauded the efforts of the Dravet Syndrome Foundation, both during the Roundtable as well as in later talks they presented during AES. There is a lot of interesting research going on in several animal models and cell lines, there are some very engaged physicians, and there is increasing awareness of Dravet Syndrome among neurologists. The meeting was sponsored by Transgenomic and The Joseph and Catherine Johnson Foundation.
The night began with a preview of an awareness video intended for neurologists and encouraging consideration of Dravet Syndrome in seizure disorders with presenting signs we are all too familiar with. This video will be part of DSF’s Consider Dravet campaign, targeted at neurologists and other professionals.Then Drs. Scheffer, Nordli, and Miller engaged in a free flowing discussion of their clinical experience with Dravet Syndrome.They discussed what clinical manifestations are sufficient to diagnose Dravet Syndrome, and argued the importance of the genetic features (SCN1A and other channel mutations) and the clinical features in patients with no known mutation.
After the introductory portion of the meeting, the floor was given in turn to the researchers present. Dr. Auerbach began with a description of his study of SUDEP in mouse and pluripotent stem cell models. His team believes that SCN1A mutations in cardiac (heart) muscle may predispose to irregular pacing (arrhythmias) that may precede SUDEP. Dr. Auerbach’s team demonstrated hyper excitability in muscle cells with an SCN1A mutation, and showed arrhythmias preceding SUDEP in mice.
Dr. Ziburkus recapped the prevailing notion that a loss of inhibition in neural systems leads to Dravet Syndrome. Specifically, a class of neurons influenced by the neurotransmitter GABA, known as GABAnergic interneurons, is thought to be less than fully functional in Dravet Syndrome. Because these interneurons normally quiet things down, their disorder leads to increased excitability. But in addition to the loss of inhibition, Dr. Ziburkus team believes there may be some baseline increase in excitability in Dravet Syndrome, independent of the faulty interneurons. His team showed the effect of administration of the neurotransmitter adenosine in decreasing this baseline excitation in a hyperthermia induced seizure model.
Dr. Kearney argued that the context in which an SCN1A mutation exists matters. Her team demonstrated differences in seizure threshold between mouse models with SCN1A mutations and is investigating the possibility of other gene mutations in the inhibitory or excitatory neural networks, which may increase or decrease the likelihood of seizures.
Dr. Hammer began with a moving story of his daughter who suffered an intractable seizure disorder. He related the feelings of isolation, the frustration of no diagnosis, and the pain of losing his daughter to SUDEP. The experience inspired him to use DNA sequencing technology to screen for mutations in children with undiagnosed severe epilepsies. He began with his own family and ultimately narrowed down the possibilities to an SCN8A mutation. He then studied 10 more children and sequenced the portion of their DNA that actually codes for proteins, known as the exome, as much of DNA provides structure or is of unknown function. Dr. Hammer’s team found several new gene variants in the patients, and continues the search for more.
Such exome sequencing yields a large number of variants, reflective of the diversity between individuals. Dr. Poduri described a similar study in her lab. In a laborious process, the candidate variants are narrowed down to those found uniformly across species, those known to be associated with neural function and/or epilepsy, until only a few candidate gene mutations remain. The hope is to provide understanding and characterization of epilepsies and perhaps find therapeutic targets.
Dr. O’Dowd discussed her modeling of human sodium channelopathies in a Drosophila (fruit fly) model. It is easier to induce mutations in flies, than in mice or other animal models, allowing for a study of more mutations in less time. The flies also provide a simplified model of neural networks. Her experiments showed some seizure inhibition with administration of serotonin reuptake inhibitors, a current and interesting area in Dravet Syndrome research and treatment.
The Intellimedix presentation began with an introduction from Daniel Fischer, father of a child with Dravet Syndrome. Intellimedix is engaged in a gene-sequencing project with Dr. Laux. Dr. Skolinick described a computer based computational analysis tool they use to virtually test drugs that may be useful in seizure disorders. The thought is that the virtual model could quickly narrow down possibilities to promising candidates for testing in animal models such as fruit flies, zebra fish, and mice.
It was encouraging to see the enthusiasm of the roundtable participants and the breadth of ongoing research. Informal discussions continued on to the bar, allowing the networking and sharing of ideas that may one day help our children.
2011 AES Research Roundtable
The second annual DSF Research Roundtable was held on December 1, 2011 in Baltimore, MD. This meeting, held at the American Epilepsy Society Conference and sponsored by The Joseph and Catherine Johnson Family Foundation and Transgenomic Molecular Laboratory, brought together over forty international researchers, geneticists, neurologists, and other professionals with a strong interest in Dravet syndrome and related epilepsies. This year we were pleased to also include members of ICE Alliance, Dravet Syndrome UK, DSF Spain, and The Charlie Foundation To Help Cure Pediatric Epilepsy among our guests. The purpose of this annual roundtable is to establish a research roadmap to guide the DSF in funding research projects that address the critical challenges of this syndrome and to determine which projects will offer the most promising breakthroughs at the fastest pace. This strategy of prioritizing research needs by a consortium of experts allows the DSF to facilitate the development and implementation of better treatment options.
Lori O’Driscoll, DSF President, welcomed attendees to the meeting with a presentation of the video “Braxton’s Story for Piper’s Song.” Dr. Jack Parent of the University of Michigan and Dr. Sooky Koh of Children’s Memorial Hospital then moderated the scientific portion of the meeting. This began with three keynote presentations: Dr. Miriam Aza discussed the DSF Spain genetic testing program; Dr. Ingrid Scheffer provided a review of Dravet syndrome; and Dr. Linda Laux gave an overview of current and emerging therapies.
Investigators who received 2010 or 2011 DSF Research Grant Awards then reported on their recent progress. Allison Althaus, a senior graduate student in Dr. Parent’s lab, presented her results on a project to investigate readthrough treatment of Dravet syndrome caused by nonsense SCN1Amutations. Dr. Sooky Koh gave an update on her project to address the role of brain inflammation after a seizure, introduce dietary intervention, and use enriched environments in a murine seizure model. Dr. Scott Baraban presented his work using a zebrafish SCN1Amutant model to screen for novel therapeutic agents to treat Dravet syndrome. Dr. Jane Hsiao, representing OPKO Health Inc., presented work on a novel technology aimed at increasing SCN1A-encoded protein production in brains of Dravet syndrome patients.
The final part of the program consisted of a data blitz by current researchers in Dravet syndrome and related fields. Dr. Francke Kalume presented work on the mechanism of sleep disturbances in a mouse model of Dravet syndrome. Dr. Lori Isom (in collaboration with Dr. Parent and Dr. Miriam Meisler) used human induced pluripotent stem cell neurons to reveal a novel mechanism of Dravet syndrome caused by SCN1Amutations. Dr. Heather Mefford reported progress in identifying genetic copy number variations in patients with inherited epilepsy. Dr. Alica Goldman showed her recent progress in extracting genetic information from multiple types of patient tissue samples. Finally, Dr. Tara Klassen gave an overview of her team’s recent publication showing a number of novel human mutations linked to inherited epilepsy.
Overall, the program was a great success, providing not only new scientific information, but also invaluable opportunities for networking between academic and industry scientists, physicians, and parents of children with Dravet syndrome.
Dr. & Mrs. Morton Sperling