PAST RESEARCH ROUNDTABLES
By Nicole Villas
DSF Board President
DSF hosted its 9th annual Research Roundtable on November 29, 2018, in conjunction with the American Epilepsy Society’s annual meeting in New Orleans, Louisiana. The roundtable has become the highlight of the meeting for many professionals, and we are pleased to see attendance grow each year.
Dr. Jack Parent, Dr. Lori Isom, and Dr. Scott Baraban organized the speakers and moderated the evening, which consisted of 6 presentations, question and answer time, and a brief discussion period. Links to the speakers’ most recent AES poster abstracts, or published literature where appropriate, are included after each description.
Evangelos Kiskinis, PhD, of Northwestern University, received a grant in 2016 from DSF to study patient-specific induced pluripotent stem cells (iPSCs). He presented his work on these cells, which involved creating an “isogenic” control population by editing the patient’s mutation out of their iPSC before differentiating them into different types of neurons and other cells. This allows the team to study a single patient’s mutation in the context of that patient’s particular genetic makeup, called the “genetic background,” a task that is difficult to do in a mouse model of Dravet syndrome. Distinct differences were observed between the healthy control populations and the mutated populations. Using a similar CRISPR/Cas9 editing procedure, they were able to study isolated neurons and how they compromised their ability to interact with control neurons. Dr. Kiskinis also presented the concept of extending his recently published “Optopatch” technique to SCN1A-mutated neurons. The optopatch technique involves stimulating neurons and imaging their responses with light, which could be useful in higher throughput screening of drugs.
Lori Isom, PhD, of the University of Michigan, presented her lab’s work with Stoke Therapeutics’ Targeted Augmentation of Nuclear Gene Output (TANGO) in a Dravet syndrome mouse model. TANGO is a potential disease-modifying approach that increases production of healthy sodium channels by increasing the cell’s editing efficiency of the Scn1a gene transcript. The cell normally destroys a percentage of transcripts after reading the Scn1a gene through nonsense-mediated decay (NMD). TANGO rescues a portion of those transcripts headed for NMD, instead sending them outside of the nucleus to be translated into healthy sodium channels. Because it uses antisense oligonucleotides (ASOs), which contain a specific sequence of nucleotides unique to Scn1a, it selectively upregulates Scn1a without affecting the other sodium channels. This approach has proven extremely successful in increasing Scn1a mRNA and Nav1.1 sodium channels in a Dravet syndrome mouse model to the levels seen in healthy mice. When injected directly into the mouse brain shortly after birth, TANGO rescued 99% of the animals from SUDEP, or sudden unexpected death in epilepsy, which usually occurs in approximately 60% of animals by 35 days after birth. Furthermore, when healthy mice were treated with TANGO, no obvious adverse events were recorded, suggesting TANGO does not over-upregulate Scn1a expression. In an attempt to mimic what might happen in humans, when the disease is not found until after the first spontaneous seizure, Dr. Isom’s team is injecting the mice around two weeks of age (when seizures normally begin in the mice), and preliminary results show that a single dose rescues a subset of the mice. Further studies on dosage, timing, and seizure effect are needed, as well as many other studies before this might be ready for a small test in human patients.
Joseph Sullivan, MD, of the University of California at San Francisco, gave an update on Zogenix’s formulation of fenfluramine, now named “Fintepla.” Two Phase 3 pivotal trials were conducted: one with patients who were not taking stiripentol, and one with patients taking stiripentol. The first study looked at both a low dose and a high dose of fenfluramine, while the second study included a single dose of fenfluramine. In the first study, patients taking the high dose of fenfluramine had a 64% reduction in mean number of monthly convulsive seizures. 75% of patients on high dose experienced at least a 50% reduction in seizures and 45% had more than a 75% reduction, including 25% that were nearly seizure free. Similarly, in the second study patients experienced a 55% reduction in mean monthly seizures, and 54% had at least a 50% reduction in seizures, and 34% had more than a 75% reduction, with 14% being nearly seizure free. Common side effects included reduced appetite, diarrhea, fatique, lethargy, and insomnolence. Because fenfluramine was pulled from the market because of cardiac concerns including valve thickening or valvulopathy, patients in the trials underwent frequent cardiac workup. Echocardiograms performed several times throughout both the blind portion of the trial and the nearly 3 year open label extension revealed no cases of valvulopathy or pulmonary hypertension as of March 2018. Beyond seizures, the caregiver’s global impression of change was “much improved” or “very much improved” in 55% of patients on high dose and 41% of patients on low dose. The Behavioral Rating Inventory of Executive Function (BRIEF) index showed a significant improvement in the high dose group, which could be related to seizure reduction or direct action of fenfluramine itself. Zogenix expects to submit their New Drug Application (NDA) to the FDA in the first quarter of 2019.
Alex Nord, PhD, of the University of California at Davis, received a 2015 DSF Research Grant to study regulatory mechanisms of Scn1a expression in a mouse model of Dravet syndrome. He presented his work, which focused on the functional requirement for one specific regulatory element near Scn1a, named “h1b,” that were discovered in 2007. Selectively deleting this regulatory element affected Scn1a expression in the mice, and deleting both copies of h1b was lethal. These studies have demonstrated the h1b element is required for Scn1a expression in the brain, with studies on how h1b regulates Scn1a expression ongoing.
George Richerson, MD, PhD, of the University of Iowa, presented his work on a respiratory mechanism of SUDEP in a mouse model of Dravet syndrome. The mice, modeled from a human SCN1A truncating mutation, suffer from a high rate of SUDEP, apparently due to seizure-induced respiratory arrest, usually by age 60 days. His team monitored mice during spontaneous seizures and hyperthermic seizure induction and found that breathing stops first, followed by slowed heartrate (bradycardia). In addition, the mice breathe less efficiently for long periods after a seizure, and most SUDEP and nonfatal seizures occur in the mice at night. They often have a flurry of seizures prior to SUDEP, often after a period of relative seizure infrequency. While a ketogenic diet reduced SUDEP in the mice by about 50%, it did not reduce nonfatal seizures, and they breathed neither deeper nor faster. Additionally, the mice have prolonged apneas associated with bradycardia (slow heart rate).
Chad Frasier, PhD, of the University of Michigan, presented his work using cardiomyocytes (individual heart cells) that, when grown in a dish, contract upon external stimuli and are responsible for the repolarization phase and propagation of the action potential. Although SCN5A is the most predominantly expressed sodium channel in the heart, the others (including SCN1A) are present as well. Using cells taken from 4 human patients, they created cardiomyocytes (iPSCs) that are patient-specific. The cells in the dish “beat” synchronously at a significantly faster rate than the controls. They are also prone to beating twice after stimulation instead of just once, like the controls. To double check the reliability of the model, they took one of the healthy control cells and induced a mutation, and when those cells were developed into cardiomyocytes, they exhibited the same abnormalities in sodium current, despite there being no history of cell damage from seizures or Dravet syndrome, confirming that haploinsufficiency (lacking ½ of the healthy SCN1A genes) is the cause of the abnormalities.
Dr. Baraban closed the evening with a brief discussion about the future of Dravet syndrome research and asked the professionals in attendance to consider, as gene therapy science progresses, where might be the best place to test these therapies, and which models might prove most useful.
DSF expresses our sincerest gratitude to Dr. Parent, Dr. Isom, and Dr. Baraban, and thanks the speakers and all of the attendees who took time from their busy AES schedule to dedicate the evening to our Dravet syndrome Community!
By Nicole Villas, DSF Board President
DSF’s 8th Annual Research Roundtable was held on November 30th, 2017 in Washington D.C. just before the American Epilepsy Society’s Annual Meeting. This meeting started in 2010 as a brainstorming session for the few researchers working on Dravet syndrome and has grown to include over 150 attendees. Scientific Advisory Board Chair Dr. Jack Parent, of the University of Michigan, and Scientific Advisory Board member Dr. Scott Baraban, of the University of California, San Francisco, moderated the evening, made possible by sponsors Greenwich BioSciences, Zogenix, and the Bresler Family. Six speakers presented their most current work, after which the entire group discussed where they hoped to see Dravet syndrome in 10 years.
The first speaker, Jacy Wagnon, PhD, received a DSF Post-Doctoral Fellowship award in 2014. She presented a comparison between Scn1a and Scn8a mutant mice and their messenger RNA (mRNA) expression after seizures. mRNA is the transcript that carries a given gene’s instructions to a place in the cell where the transcript can be translated into a protein. Studying mRNA expression helps us understand which genes are being expressed under certain circumstances such as seizures. Genes whose expression is altered after seizures may suggest possible therapeutic avenues. She found some transcripts that were dysregulated after seizures in the two mouse models as well as in induced epilepsy models, indicating that therapeutic targeting of these mRNAs may be applicable to a broad range of seizure disorders.
Aliesha Griffin, PhD, received a DSF Post-Doctoral Fellowship award in 2016 for the optimization of clemizole. Dr. Griffin explained how her current work in the Baraban Lab at UCSF stemmed from the results of the high throughput screening done on zebrafish scn1lab larvae. During screening, 3 compounds showed potential use in treating seizures in the mutant zebrafish: clemizole (an antihistamine no longer produced in the USA), lorcaserin (Belviq, an FDA-approved weight loss medication), and trazodone (an FDA-approved sleep medication). Her work over the past year has focused on removing the antihistamine component of clemizole, creating analogs of the molecule, and determining the mechanism(s) of action.
The third speaker, Jeff Calhoun, PhD, also received a DSF Post-Doctoral Fellowship award in 2016. He has been mapping neuronal activity in a mouse model of Dravet syndrome by measuring the expression of another gene, c-Fos, that is expressed when neurons fire. Dr. Calhoun examined hippocampal neuronal activity and studied the time signature of c-Fos expression in different types of seizures.
Dennis Lal, PhD, received a DSF Research Grant in 2016 for a computational analysis of SCN1A mutations in human patients to determine whether pathogenicity can be predicted. He presented his findings and compared and contrasted the areas of SCN1A and SCN2A where mutations are more likely to result in disease symptoms.
Prof. Ingrid Scheffer, MD then brought the evening back to the clinical patient, summarizing three studies on sleep, mortality, and a rare SCN1A syndrome that is even more severe than Dravet syndrome. Prof. Scheffer described the nature of the sleep problems and suggested melatonin may be underutilized. In terms of mortality, she described several cases of status epilepticus with resulting cerebral edema and death within several days of the SE. Although interventions to reduce pressure in the brain were unsuccessful, she stressed the need for more urgent imaging and rapid addressment of brain pressure. Finally, she described an “SCN1A Early Infantile Epileptic Encephalopathy” that begins earlier in infancy than Dravet syndrome, includes tonic seizures and spasms (not common in DS), is associated with severe movement disorders, and results in early and profound delays. Several patients with this phenotype were found to have the exact same mutation, Thr226Met.
Finally, Ethan Goldberg, MD, PhD, presented novel methods for imaging seizures in an experimental model of DS. Through an optical imaging device, his laboratory is able to not only conduct an EEG on an awake, behaving mouse actively running on a treadmill, but optically “see” what is happening to specific subsets of neurons before, during, and after a seizure in real time.
Dr. Parent and Dr. Baraban concluded the evening with a discussion of whether the treatments scientists have come up with over the years actually prevent, halt the progression of, or even reverse the course of Dravet syndrome if given early enough. Members of the audience weighed in on what intervention may look like and what would be required to make it a reality.
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.