Special thanks to DSF Board President and Scientific Director, Nicole Villas, for sharing an overview of the 2019 DSF Research Roundtable in this week’s blog post.
We are excited to be able to share the impact of our community’s ongoing support!
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 in our commemorative 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. You can read the abstract at this link.
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 at this link.
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, at this link.
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.