15th Annual DSF Research Roundtable - 12/5/24
This annual meeting, held at the American Epilepsy Society (AES) Conference, brings together researchers, geneticists, neurologists, and other professionals with a strong interest in Dravet syndrome and related epilepsies. The purpose of this roundtable is to establish a “research roadmap” to guide DSF in funding research projects that address the critical challenges of this syndrome and which will offer the most promising breakthroughs at the fastest pace. By allowing this consortium of specialists to prioritize research needs, DSF can facilitate the development and implementation of better treatment options.
Our 15th annual Research Roundtable will take place in Los Angeles, CA on December 5, 2024. Stay tuned for more details.
This meeting is by invitation only. If you are a professional interested in attending the DSF Research Roundtable and would like more details, please contact us.
If you are interested in sponsoring the 2024 Research Roundtable, you can view the sponsorship levels here.
The 14th Annual Research Roundtable took place in Orlando, Florida on the evening of November 30, 2023. DSF’s Scientific Director, Veronica Hood, PhD began the night by introducing the 2023 DSF Grant Awardees, which included funding for eight grants totaling $2,475,000, focusing across areas of research related to increasing our understanding of the impact of genetic background on the clinical presentation of patients with Dravet syndrome, novel disease modifying therapies, neuronal communication, characterization of novel animal models, cardiac function, measurement of clinical outcomes, and sleep.
DSF Board President, Ted Odlaug, PhD preceded the scientific program by speaking about the journey of his granddaughter, Anna, who has Dravet syndrome. Dr. Odlaug emphasized the difficult trial-and-error approach to medication and therapy selection that Anna has had to endure, often experiencing breakthrough seizures and hospitalizations. While the hope for the future is to have targeted therapeutics that effectively treat seizures as well as the other symptoms of Dravet syndrome, Dr. Odlaug underlined the need for improved treatment algorithms in the short-term that could allow for more directed, personalized treatment plans.
The Scientific Program was moderated by Jack Parent, MD and Lori Isom, PhD the co-chairs of the DSF Scientific Advisory Board and experts in the field of epilepsy and Dravet syndrome.
Joseph Sullivan, MD from the University of California San Francisco began the scientific program by presenting the most recent updates to characterizing the natural history of Dravet syndrome. Dr. Sullivan emphasized the importance of natural history studies not only to improve the clinical understanding of Dravet but also to inform clinical studies investigating novel therapeutics. Dr. Sullivan presented data from 3 examples of such efforts in Dravet syndrome. The first source was a recent publication (Makiello et al, 2023 Epilepsia) from a 10-year follow-up study that included 68 patients with Dravet syndrome focused on predictors of quality-of-life related outcomes. They found that quality of life was greatly impacted by epilepsy severity and behavioral symptoms, consistent with what is often prioritized as a concern for families. Dr. Sullivan also presented data from two prospective studies sponsored by Stoke Therapeutics, the BUTTERFLY Study, and Encoded Therapeutics, the ENVISION Study. These studies used standardized assessments to collect information on developmental domains related to behavior, communication, and motor skills and the data between the two studies showed consistent results that many of these deficits in development occur early, although some measures like communication and fine motor function may not show declines but rather plateau while age-matched peers may still be gaining in skills that further widen the gap. Other measures, such as behavior and gross motor skills, are more likely to decline over time. The goal is that with this more detailed characterization of the outcomes in Dravet syndrome we will be able to show that future targeted therapies can change the natural history of the disease course for patients.
The next talk of the evening came from 2020 DSF Grant Awardee Cameron S. Metcalf, PhD of the University of Utah. Dr. Metcalf presented on his laboratory’s exploration of mechanisms that may contribute to sudden death in a mouse model of Dravet syndrome. Sudden Unexpected Death in Epilepsy (SUDEP) is a major risk for patients with Dravet syndrome, and SUDEP has been linked to both respiratory and cardiac dysfunction, often, but not always following a seizure event. Dr. Metcalf has been investigating respiratory activity in a mouse model of Dravet syndrome, probing changes in breathing at rest and following a seizure, characterizing structural and molecular changes in lung architecture, as well as in relevant brain regions that control respiration. While his lab initially set out to look at inflammation that may be involved in these processes, the investigations have led to new directions and novel questions that they continue to investigate related to breathing, SUDEP, and Dravet syndrome. They are currently continuing to investigate how their findings may change across development and the potential role of energy metabolism in these processes.
Anna G. Figueroa, BS, a PharmD Candidate from the laboratory of Manisha Patel, PhD at the University of Colorado Anschutz Medical Campus gave an update on a 2021 grant award to Dr. Patel and co-investigator Dr. Kelly Knupp. Metabolic dysfunction has been identified in models of Dravet syndrome as well as in patient samples, and the success of the ketogenic diet as a therapy has additionally underlined the importance of investigating metabolism as a potential therapeutic target. Their project involved establishment of lymphoblast cell lines (LCLs) from patients with Dravet syndrome and subsequent analysis for changes in metabolic function. Despite being a peripheral blood cell, metabolic changes deficits indicating impaired mitochondrial function could be detected between patients and controls and some preliminary work also suggested that some changes could also be correlated with medications patients were utilizing. They are still expanding the number of cell lines they have investigated and also following up on new lines of inquiry that have emerged after some additional projects investigating gene expression changes in the same cell lines.
The final scientific talk of the evening was from Moran Rubenstein, PhD of the University of Tel Aviv presenting on a 2020 DSF-funded project done in collaboration with Eric J. Kremer, PhD of Institut de Génétique Moléculaire de Montpellier examining viral-mediated expression of the SCN1A-encoded sodium channel, Nav1.1, as a genetic therapy in a mouse model of Dravet syndrome. One of the barriers to a straightforward gene-replacement therapy for Dravet syndrome is the large size of the SCN1A gene, which outsizes any of the currently utilized delivery vectors for human genetic therapies. They tested a large canine adenovirus vector (CAV) as a solution given its large size capacity, ability to target neurons, reduced immunogenicity, and long-term expression following injection. They showed that this vector could effectively deliver SCN1A to the brain, and that, even with limited numbers of targeted cells, they could greatly improve survival and reduce susceptibility to seizures both when intervening at seizure onset as well as at later developmental stages. They additionally saw improvements in some behavioral tasks following treatments, suggesting this approach could modify the disease course. Dr. Rubenstein and Dr. Kremer have published their work and are continuing to investigate more about the cell types that are most important to target with this approach, the developmental windows for treatment, and efficacy. You can read more about their published work on this this topic here.
Bookending the scientific program, Dr. Odlaug began the discussion portion of the evening by again reflecting on his granddaughter Anna’s uncertain journey through a list of medication combinations, asking the audience how this trial-and-error approach might be improved for patients with Dravet syndrome. A variety of efforts are underway that will hopefully move the needle on treatment, beyond the development of novel therapies. DSF just announced funding for a $1 million grant to Ingo Helbig, MD and Ethan M. Goldberg, MD, PhD at The Children’s Hospital of Philadelphia (CHOP) to analyze large datasets from whole genome sequencing paired with clinical data. Probing the information gathered in these datasets may be able to reveal novel insights into groups of patients that have unique clinical features or responses to medications. Additionally, there remains interest in the further development of cellular models that could utilize patient-derived cells to answer questions about therapeutic impacts. This could involve the further advancement of induced pluripotent stem cell (iPSC)-derived neuronal cultures, as well as the investigation of other cellular models, such as the LCL studies presented by Anna Figueroa from the Patel lab during the evening’s scientific program. Animal models have also been incredibly important for drug discovery, and researchers at the University of Utah are working on teasing about polytherapy approaches in a mouse model of Dravet syndrome. Lastly, the audience discussed the importance of data sharing and seeking ways to be more open in this arena, particularly with existing silos of clinical data.
The evening’s discussion brought forth a few key themes. Science has made some tremendous advancements, but the needle has still not moved enough on patient outcomes. Hopefully, we are beginning to see the payoff of the technological advancements as genetic based therapies are reaching human clinical trials for Dravet syndrome. The community should continue to invest significant time and resources into the development of therapies that hold the potential to be disease modifying. However, in addition to investing in next-generation therapeutic development, there are still some holes that exist in our basic science knowledge and research toolkit that require attention. Sometimes, this may mean taking a step back to basics, supporting the development of science tools that can further tease apart the neurobiology related to the onset and progression of Dravet syndrome. While these studies may be initially more removed from impact on clinical outcomes, they will ensure that the next generation of therapies can be increasingly more precise in their design and application.
The 13th Annual Research Roundtable took place in Nashville, Tennessee on the evening of December 1, 2022. DSF’s Scientific Director, Veronica Hood, PhD began the night by introducing the 2022 DSF Grant Awardees, which included 5 grants totaling $690,000, focusing on SUDEP, non-seizure comorbidities, and furthering our understanding of the neuronal networks that impact the symptoms of Dravet syndrome. The Scientific Program was moderated by Jack Parent, MD and Lori Isom, PhD the co-chairs of the DSF Scientific Advisory Board and experts in the field of epilepsy and Dravet syndrome.
Danielle Andrade, MD, MSc, FRCPC (University of Toronto) opened the night discussing her DSF-funded research looking at a multimodal assessment of adults with Dravet syndrome. Strikingly, the study recruited 92 adult patients with Dravet syndrome across 8 countries to participate and was able to evaluate 60 submitted videos for assessment of gait and movement. The study further confirmed the progression of impacts on these measures as adults with Dravet syndrome age. Dr. Andrade’s work has identified common features in these measures to some movement features of Parkinson’s leading to the success of levodopa trials in some patients.
Guoping Feng, PhD (MIT) shared his laboratory’s work using genetically engineered marmoset models to explore behaviors related to neurodevelopmental disorders. While flies, fish, and mice are some of the most common animal models used in Dravet syndrome, there are many aspects of the disease that are not well represented by these animal models, particular related to behavior and advanced cognitive processes. Dr. Feng’s work gave an example of how these aspects have been modeled in the marmoset for other related disorders to spur conversations around animal models in Dravet syndrome.
Michael Hammer, PhD (University of Arizona) and Ted Cummins, PhD (Indiana University- Purdue University Indianapolis) presented their collaborative work that identified an SCN1A variant that modifies the pathogenicity of a more severe disease-causing variant in another locus within SCN1A. This work highlighted the many ways in which other parts of the genome can impact disease-causing mutations in SCN1A, even from SNPs within the same gene.
Paige Whyte-Fagundes, PhD (University of California San Francisco) presented some of her postdoctoral work in Scott Baraban’s lab using the scn1lab mutant zebrafish to evaluate antiseizure drugs that may have the potential to translation to human therapies. Importantly, this model has already led to therapies that are being tested in human clinical trials, highlighting the strength of the zebrafish in drug discovery.
Nael Nadif Kasri, PhD (Radboud University Medical Centre) discussed his approach to assessing network activity in neurons derived from the cells of patients with Dravet syndrome using micro-electrode arrays. While the models still need to be developed further to introduce more complexity to the neuronal subtypes, they have been able to model a hypo-active and desynchronized network dependent on SCN1A mutation-type. They are testing this model as a potential screening tool for anti-seizure medications with the strength of being able to test with the unique genetic background of each patient.
Joanna Mattis, MD, PhD (University of Michigan) shared her work from her fellowship with Ethan Goldberg at CHOP using optigenetics to manipulate neuronal activity and characterize cortico-hippocampal circuit dysfunction in a mouse model of Dravet syndrome which has helped to uncover that increased excitability may contribute to the overall network disfunction as opposed to solely a loss of inhibition in SCN1A haploinsufficiency.
Ashleigh Schaffer, PhD (Case Western Reserve University) finished the evening describing her research approach utilizing differentiated interneurons derived from H9 cells containing representative patient mutations in SCN1A. While the individual genetic background of each patient is likely important to the overall disease presentation, this approach allows for a more straightforward investigation of SCN1A variants in direct comparison to one another and assessments of activity can be made using the same micro-electrode arrays discussed in Dr. Kasri’s presentation. Dr. Schaffer also discussed a collaboration with UMBio to investigate trans-splicing of pre-mRNA as a potential therapeutic approach to editing out causal SCN1A mutations from RNA transcripts.
The 13th Annual DSF Research Roundtable wrapped up as usual with a large group photo- notably it seems to get harder each year to fit the crowd into a single frame. Just this alone represents the amazing work DSF has done in convening all of the stakeholders in one place to foster collaboration and work with speed towards improved patient outcomes.
On the evening of Thursday, December 3, 2021 the Dravet Syndrome Foundation hosted the 12th annual Research Roundtable just prior to the American Epilepsy Society’s 2021 Meeting in Chicago, Illinois. Following the 2020 virtual-only event, it felt electric to be gathered together in person to discuss the advances in Dravet syndrome research. Presentations focused on topics from clinical assessment of behavioral issues to development of disease modifying therapies delivered by excellent speakers on the cutting edge of research efforts. After a welcome from DSF’s Scientific Director, Veronica Hood, PhD, the night was moderated by Lori Isom, PhD and Jack Parent, MD, the co-chairs of DSF’s Scientific Advisory Board and experts in the study of Dravet syndrome. Dr. Isom began the evening by announcing the 2021 DSF grant awardees, which are detailed in this blog.
Deborah Bilder, MD from the University of Utah began the night by discussing a tool she developed called the “Sources of Distress.” This tool was developed to help determine the reasons behind difficult behaviors in individuals with intellectual or developmental disabilities that may impede their ability to effectively communicate why they are agitated. Dr. Bilder underlined some of the cycles of treatment for acute agitation that are not effective for chronic agitation, often making treatment more complex in these individuals. The tool uses a questionnaire with branching logic through a computerized algorithm to identify sources of behavioral issues. The tool is free to access and can be filled out by parents or caregivers. An automated report is generated that can be used as a tool to help facilitate discussions with a health care provider managing the patient’s care. Dr. Bilder is also available to consult directly with health care providers who may want further guidance on building a care plan following review of the report. The tool can be access at the Utah Department of Health website.
We next heard from Gaia Colasante, PhD from San Raffaele Hospital about the potential for reversibility in Dravet syndrome. Dr. Colasante presented work using a novel mouse model of Dravet syndrome where the mutation in the SCN1A gene can be corrected using special genetic tools. They tested the impact of correcting the mutation at day 30 and day 90 of age, representing two time points after the onset of symptoms in this mouse model. At both ages, reversal of the genetic mutation in SCN1A resulted in reduction of symptoms, including seizures, behavioral deficits, and mortality, as well as normalization of the gene expression profile within the brain. This is an important proof-of-concept that gene-based therapies may be effective even well after the onset of symptoms in Dravet Syndrome.
Chris Ahern, PhD from the University of Iowa spoke next about his work to overcome premature stop codons that lead to the truncation of gene products. His lab’s approach uses tRNA to literally “read through” the premature stop codons that are created from nonsense muations, turning a nonproductive mRNA product back into a working transcript that can produce healthy copies of the gene. This approach is being investigated preclinically for potential applications in Dravet syndrome by Tevard Biosciences in an effort to restore levels of the Nav1.1 sodium channel in patients carrying nonsense mutations in the SCN1A gene. What is really powerful about this approach is the broad potential for this read-through technology to work in a gene-agnostic way that could create genetic-based therapies for any disorder caused by a premature stop codon.
Lin Mei, PhD from Case Western Reserve University School of Medicine presented on work to better understand modifications of the Nav1.1 sodium channel. They have discovered that a protein modification, called neddylation, can affect the stability of the Nav1.1 protein. They found that impairment of the neddylation pathway can decrease the levels of Nav1.1 protein, suggesting that neddylation helps to stabilize and prolong the lifetime of Nav1.1 in the cell. This work opens a new line of investigation into potential new causes of SCN1A-related epilepsy, perhaps through mutations that affect neddylation sites, as well as potential lines of investigation for treatment approaches through the enhancement of neddylation to possibly increase stability of the Nav1.1 protein.
Jennifer Kearny, PhD from Northwestern University Feinberg School of Medicine was the last speaker of the night and she focused on the work her lab has pioneered in understanding genetic modifiers of SCN1A. There are many questions about the variability seen in the clinical presentations of patients with Dravet syndrome and how the rare instances of inherited SCN1A mutations may result in family members carrying the mutation but presenting across the range from unaffected to the clinical presentation of Dravet syndrome. Dr. Kearney’s work in mouse models has shown that the background genetics of unique mouse strains can affect the presentation of symptoms in SCN1A +/- mice. They have discovered some several genes and RNAs that may modify the impact of SCN1A mutations through comparison of gene expression profiles between strains. These findings have important implications for our understanding of Dravet syndrome and may inform future treatment approaches.
Scott Baraban, PhD, a member of the DSF Scientific Advisory Board, closed the evening out by leading some discussion of what sort of big questions the field may want to investigate more closely. Discussion turned to brainstorming about the ways the field could expand upon Dr. Kearney’s mouse work using patient samples to better understand the genetics that impact Dravet syndrome beyond SCN1A. Such studies would be a tremendous undertaking, but it’s a topic that certainly warrants more discussion. Ending the Research Roundtable with exciting topics of interest to push forward in the new year was a great finish to the evening that set our sights on the future. We look forward to gathering next year to see what progress 2022 brings!
The Dravet Syndrome Foundation hosted our 11th annual Research Roundtable on December 3rd, 2020, the evening prior to the annual American Epilepsy Society (AES) Meeting. Given the current COVID-19 pandemic, the events were held virtually this year. Despite the limitation of not being in person, the roundtable was larger than ever and brought together expert scientists and clinicians who are leaders in the field of Dravet syndrome research and treatment. We heard presentations from several of these experts, including some previous-year DSF grant recipients.
Lori Isom, PhD, co-chair of DSF’s Scientific Advisory Board, began the night by welcoming us all to the roundtable over video-stream from beside a cozy fireplace. She went on to acknowledge the DSF staff, Board of Directors, and the Medical and Scientific Advisory Boards for all they do to support research for Dravet syndrome.
Following Dr. Isom’s introduction, Veronica Hood, PhD spoke on behalf of DSF to thank all of the 2020 Research Roundtable sponsors who made the night possible, and to announce the 2020 grant recipients. You can read more about the 2020 awardees here.
Danielle Andrade, MD, Msc, FRCPC from Toronto Western Hospital at the University of Toronto began the night speaking about several projects to better describe the presentation of comorbidities in adults diagnosed with Dravet syndrome. She has been studying the longitudinal progression of gait abnormalities and behavioral skills. While the study size is still small and in early stages, these types of studies are the first step towards improved treatment approaches for adults with Dravet syndrome. Part of this project was presented as a poster at the AES meeting.
We next heard from Ethan Goldberg, MD, PhD from Children’s Hospital of Philadelphia and the University of Pennsylvania describing how different subsets of neurons in an Scn1a mouse model of Dravet syndrome are differentially impaired during specific windows in development. As work from his lab has previously indicated, excitatory neurons may show impairment independent of the dampened excitability of inhibitory neurons, suggesting the mechanisms of disrupted brain development are quite complex in Dravet syndrome. The developmental changes in signaling in the Scn1a mouse model may imply there are critical windows in development where intervention may be most impactful.
Our third speaker of the evening was Rajeswari Banerji, Phd, a postdoctoral trainee in Dr. Manisha Patel’s laboratory at the University of Colorado. Dr. Banerji received a postdoctoral fellowship from DSF in 2018, and this presentation reported key findings from that work, including targeting of the glucose metabolism pathway as a therapeutic approach for Dravet syndrome. She identified a drug that modulates the gluconeogenesis pathway can reduce seizures and restore metabolic function in a zebrafish model of Dravet syndrome. Given the effectiveness of metabolic treatments such as the ketogenic diet, this approach could potentially leverage the same principles to reduce seizures in Dravet syndrome. This work was also presented as a poster at AES.
Sharon Swanger, PhD from the Fralin Biomedical Research Institute at Virginia Tech spoke about thalamic synapse dysfunction in an Scn1a mouse model of Dravet syndrome. Dr. Swanger described impacts on both GABAergic and glutamatergic neuron populations, and she is using the specific expression patterns of unique glutamatergic signaling receptors to further stratify the affected neuronal populations. This work was part of a 2-year DSF research grant Dr. Swanger was awarded in 2018.
Our last presentation of the evening was from another 2018 DSF postdoctoral fellowship awardee, Jessica Chancey, PhD from Dr. MacKenzie Howard’s lab at the university of Texas at Austin. Dr. Chancey discussed the altered function of hippocampal neurons in the Scn1b mouse model of Dravet syndrome. She described how altered synaptic plasticity, the inability of neurons to adapt to upstream signaling, may underlie the cognitive deficits in Dravet syndrome. She was pleased to share that data from her fellowship has now contributed to an RO1-level grant from the NIH to continue studying these research topics in more detail. Dr. Chancey also presented this work as a poster at AES.
At the conclusion of the evening , Scientific Advisory Board member Scott Baraban, PhD, thanked our speakers for an excellent overview of their research. He then left us with his major take-aways for the evening, which were how pleased he is to see the next generation of young researchers stepping into the field, and how he believes DSF is a model for the rare disease community for how to push research forward. He then led a discussion of what the collective attendees saw as the most important next steps for Dravet syndrome research, with some of the most discussed topics surrounding understanding developmental treatment windows for genetic-based interventions in patients and developing larger-scale natural history studies to increase our knowledge surrounding disease presentation and progression.
All in all, the night was a successful roundtable meeting amongst those most vested in advancing research for Dravet syndrome. We are looking forward to the advancements that the future will bring for the community, and we thank the scientists and clinicians who have made those advancements possible and we look forward to continuing to make progress together.
The Dravet Syndrome Foundation was honored to host our 10th annual Research Roundtable on Dec. 5, 2019, prior to the American Epilepsy Society Annual Meeting in Baltimore, MD. The Roundtable began in 2010 as a small meeting of 10-15 scientists and parents gathered around a table brainstorming how to move Dravet syndrome research forward. This year, we welcomed a packed room of guests and five speakers to present recent research and encourage the room to think about what we can do to achieve our goal of better treatments and a cure for Dravet. Part of the celebration included a 24-page booklet describing all of DSF’s past grant awardees, their projects, results (where appropriate), and further contributions to the research landscape. You can read the summaries here: 10th Anniversary Roundtable Booklet
DSF’s Scientific Advisory Board (SAB) co-chairs Jack Parent, MD, Lori Isom, PhD, and SAB member Scott Baraban, PhD moderated the evening. Dr. Parent kicked the night off with a special 10th anniversary presentation describing how the research landscape has changed in the 10 years before DSF’s founding and the 10 years after DSF. Between 1999 and 2009 (when DSF was founded), SCN1A mutations were found in patients with Dravet syndrome and a few researchers were studying the sodium channel to understand how changes to it affect the brain. There was very little public funding for research and only a handful of publications about SCN1A, Dravet syndrome, or Severe Myoclonic Epilepsy of Infancy (SMEI), as it was referred to then. Since DSF’s founding, that bleak landscape has blossomed into a rich field composed of nearly ten times the number of basic science researchers, clinicians understanding an ever-growing population including adult patients, exponential growth in public research funding, thousands of publications on Dravet, and several new treatments approved (with several in the pipeline, including a few with potentially disease-modifying effects.) The professional community’s support has been instrumental in the steady march toward better treatments for Dravet syndrome.
Professor Helen Cross, of Great Ormond Street Hospital, kicked off the evening’s research presentations describing “Treatment algorithms moving forward.” She began with an overview of current treatments and summarized results from recent randomized controlled trials in Dravet syndrome. She discussed treatments such as bromides, the importance of avoiding contraindicated medications, and stressed that all patients are different. Indeed, her description of a 60 year old patient who developed spontaneous language after a medication change highlighted the vigilance and attention to detail required in caring for patients throughout their lives. Professor Cross described how treatment algorithms, which will need to be updated as new treatments come to the market, perhaps annually, must be data driven, approved by regulatory agencies, factor in reimbursement, and have long term data to support them.
Amy Schneider, Clinical Research Scientist with The University of Melbourne, complemented Professor Cross’s clinical treatment algorithm with a presentation titled, “Delineating the phenotypic limits of Dravet syndrome.” She posed the question: When can we diagnose DS – When all features are apparent at age 3 (which she believes is too late), after the first febrile status epilepticus event (which she believes is too early), or somewhere in between? Ms. Schneider described their in-depth study of the clinical features of a cohort of 188 patients, and how rigid definitions of DS may lead to delay in diagnosis of some patients due to subtle differences in presentations. Ms. Schneider presented a poster on this study at the AES meeting.
Louis Dang, MD, PhD, of the University of Michigan, received a postdoctoral fellowship from DSF in 2017 to study 3-dimensional neuronal organoids derived from stem cells and how their function is affected by expression of various sodium channels throughout development. His presentation, titled “Augmenting SCN1A expression by targeting upstream open reading frames,” was a direct result of that initial work and outlined how his lab is using antisense oligonucleotides to target specific areas upstream of (before) the coding region, adjusting where the ribosomes begin to translate the gene transcript.
Gemma Carvill, PhD, of Northwestern University, complemented Dr. Dang’s introduction of alternative RNA processing with a presentation titled, “Aberrant splicing of an SCN1A poison exon causes Dravet syndrome” based on progress related to her 2018 DSF Research Grant Award. While studying the genetics of patients diagnosed with Dravet syndrome without any identifiable SCN1A mutations, Dr. Carvill and her team discovered that several patients did indeed have variants, but they were in a highly conserved non-coding region of the gene and thus not identified on commercial tests. Further investigation revealed that some variants in this region cause inclusion of a particular exon that results in premature truncation of the protein, leading Dr. Carvill and colleagues to describe it as a “poison” exon. They believe that in other cell types in the body, which don’t need sodium channels, this poison exon is included to prevent expression of SCN1A, but in normal neurons, the exon is skipped and a full-length protein is created. In patients with variants in this region, the poison exon is included in more neuronal transcripts, creating prematurely truncated transcripts and fewer sodium channels. Their work supports the theory that this may be an under-recognized pathogenic mechanism and aligns with current industry attention to nonsense mediated decay, a target for treatment with antisense oligonucleotides. You can read more about their work here: Carvill et al. 2019. Am J Hum Genet.
Daniel Mulkey, PhD, of the University of Connecticut, switched gears from alternative processing of SCN1A transcripts to a SUDEP-focused presentation titled “Disordered breathing in a mouse model of Dravet syndrome” based on his 2017 DSF Research Grant Award. His team used a conditional mouse model of DS that can have an Scn1a mutation turned on or off in specific subpopulations of cells to determine the effects of the mutation on network function. Based on measurement of respiratory activity in normal air and air with high CO2 concentration, his team saw different responses and breathing activity between mice with the mutation expressed in certain neurons and those without. More information can be found in this 2018 publication: Mulkey et al. 2018. eLife.
Dr. Baraban concluded the evening with heartfelt thanks to DSF for our role in funding research and widening the field of investigators. He thanked founders Mary Anne Meskis and Lori O’Driscoll, in particular, for their early support and subsequent DSF contributions to his zebrafish lab, which has generated numerous publications, drug discovery (and now clinical development of several candidates), postdocs, and conversations in the epilepsy research community. The evening was a successful celebration of 10 years of hard work from professionals, volunteers, community members, and patients, and DSF is grateful for every person who attended to learn more about Dravet syndrome and the current state of research.
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!
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.
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.
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.
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 2014-research-roundtableimplementation 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.
The 4th annual DSF Research Roundtable was held on December 5, 2013 in Washington, DC. This gathering, held during the annual meeting of the American Epilepsy Society, and sponsored by The Joseph and Catherine Johnson Family Foundation and Transgenomic Molecular Laboratory, brought together researchers, geneticists, neurologists, parents, and other professionals with a strong interest in Dravet syndrome and related epilepsies. This year we were pleased to include colleagues from the University of Melbourne, ICE Epilepsy Alliance, the PCDH19 Alliance, DSF Spain, and Brabant Pharma among our guests. 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.
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.
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.
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.