Today’s blog post is a review of some of the topics relevant to Dravet syndrome that were presented at the annual American Epilepsy Society (AES) meeting. This was my first year attending the AES meeting and also the first year the meeting was held virtually. I learned so much and was excited by the amount of enthusiasm for the meeting that was maintained by the research community even though we were communicating from afar. I was impressed by the amount of talks and presentations that were directly related to Dravet syndrome, and I hope that in the summary below I can communicate some of the highlights. Despite the length of this post and the breadth of topics covered, it is still not a comprehensive overview! That means a great many things are happening in the research community that are all working towards a better understanding and improved treatment options for Dravet syndrome and related disorders. Feel free to read the blog in its entirety, but I have also included headings so you can skip to the topics you are most interested in reading about more.

I will start by mentioning the annual Research Roundtable that DSF hosted virtually on Thursday evening, December 3rd, just prior to the beginning of the AES meeting. There were exceptional talks from experts in Dravet syndrome, including some prior-year DSF grant awardees, that spanned basic and clinical research areas. The night ended with an energetic discussion of where the field needs to focus next and what avenues might have the largest impact on patient outcomes. If you are interested in more details of the night, you can see the 2020 meeting overview here.

The Genetics of Dravet Syndrome

Our understanding of the genetic causes of epilepsy has increased exponentially over the last 20 years. This was highlighted during the Presidential Symposium entitled Epileptic Encephalopathy: Causes, Treatment, and Outcomes. During this session, Dr. Sarah Weckhuysen gave an extensive overview of the genetics involved in epilepsy. She began by drawing attention to the recent reclassification by ILAE to distinguish between epileptic encephalopathies (EE) and developmental epileptic encephalopathies (DEE), explaining the developmental distinction is key in understanding that these disorders often are much more than seizures, and treating the seizures may not improve deficits in other areas. She went on to discuss the common genes implicated in DEEs and that many of these genes may also be related to cognitive functioning independent of seizure activity. When discussing SCN1A, she referenced a study of a selective disruption of SCN1A in a restricted brain region that led to cognitive impairment without the development of seizures, further supporting that the impacts on seizures and cognition may be independent in Dravet syndrome. These observations highlight the importance of developing more targeted therapies that treat the cause of DEEs like Dravet syndrome rather than treating just the symptoms seizures.

Polygenic Risk Scores. Despite the identification of mutations in SCN1A as the primary genetic cause for Dravet syndrome, there is still much we do not understand about how similar mutations in SCN1A can lead to such a spectrum of presentations from milder GEFS+ to more severe Dravet syndrome. A particularly exciting set of presentations on “polygenic risk scores” by Dennis Lal and Samuel Berkovic acknowledged the power of polygenic risk scores to predict the risk of developing epilepsy. Simply put, polygenic risk scores are calculated by measuring many of the common ways the genetic code may differ between people. While having these differences, or “variants,” in the genetic code are common, carrying many of these variants can add up to a higher polygenic risk score. Polygenic risk score has also been used to predict the risk of developing Alzheimer’s disease and lipid disorders. The discussion left me wondering if polygenic risk scores might be a predictor of outcomes when examined in combination with causal mutations in SCN1A. At the end of the day, both Dr. Lal and Dr. Berkovic could agree that more studies are needed with larger sample sizes, real clinical cohorts, and inclusion of individuals of diverse ethnic backgrounds.

Genetic testing and interpretations. As genetic testing continues to become more in-depth, faster, and cheaper, the time to diagnosis for many genetic epilepsies has been greatly reduced. Invitae developed the “Behind the Seizure” program to expand access to genetic testing with epilepsy gene panels to children with unprovoked seizures under the age of 8. In 2011, at the outset of this program, the average age at genetic diagnosis of an SCN1A-related disorder was 6 years, but now the average age at diagnosis is less than 2 years. This study underlines how important access to testing is for a diagnosis, and while these reported changes are excellent improvements, we know many older children and adults still struggle to access genetic testing. Hopefully the future will continue to improve access to genetic testing for all those affected by rare disease.

  • McKnight et al. “Reducing the time to diagnosis and increasing the detection of individuals with SCN1A-related disease through a no-cost, sponsored epilepsy genetic testing program.” 2020 AES. Abstract 392.

Despite access to genetic testing and receiving results that indicate a causal mutation in the SCN1A gene, it can sometimes still be difficult to determine the diagnosis between GEFS+ and Dravet syndrome. To better aid clinicians in assessing the likelihood of developing GEFS+ versus Dravet syndrome, researchers have developed an online tool that combines an SCN1A mutation score and the age of seizure onset to predict the diagnosis. Additionally, some of the same researchers who developed that tool, have also discovered that because so many of the SCN-family of genes (including the SCN1A gene) make sodium channels that are so similar in structure, known mutations in a similar spot in one of these genes can be used to predict the impact of a similarly located mutation in one of the other SCN genes. This observation can help clinicians make informed predictions about whether a particular mutation may point towards a diagnosis.

  • Brunklaus et al. “A clinico-genetic prediction model facilitates early diagnosis of Dravet syndrome.” AES 2020. Abstract 604.
  • Feng et al. “Functional data of variants at analogous positions in sodium channel genes can serve as surrogate for variant effects in related sodium channel epilepsies.” AES 2020. Abstract 175

Incidence of Dravet syndrome. Several studies have estimated the incidence of Dravet syndrome to be between 1 in 12,000 to 1 in 20,000 live births. DSF generally cites the 2015 study by Wu et al (doi:10.1542/peds.2015-1807) that estimated the incidence at 1 in 15,700. A poster presented a study from all children in the Scottish universal health care system with epilepsy from 2014-2017 that estimated the incidence of Dravet syndrome to be approximately 1 in 15,000, which closely matches the currently quoted incidence.

  • Zuberi et al. “Clinical and genomic characterisation of early childhood epilepsies.” AES 2020. Abstract 1043.

Gene-targeted Therapeutic Approaches

Therapeutic approaches that target the genetic cause of Dravet syndrome are coming to fruition. Despite the challenges that the SCN1A gene poses for classical gene therapy approaches due to the size of the gene, researchers have been developing creative approaches to overcome this barrier and uncover truly disease-modifying therapies. There was a lot of talk about gene-based approaches at AES 2020. Indeed, the presidential symposium included a talk by Dr. Amy McTague reviewing the medical modification of disease expression and encephalopathy. Dr. McTague stated that “to get to the underlying etiologies, we really have to get to a direct gene approach.” She acknowledged the potential that anti-sense oligonucleotide therapies like Stoke Therapeutics’ TANGO approach, but also indicated the challenges surrounding repeated administration of the ASO. While also acknowledging the traditional approach to SCN1A is not an option, she reviewed the approach being employed by Encoded Therapeutics to deliver an engineered transcription factor (essentially a gene that regulates the SCN1A gene and can increase healthy SCN1A expression). She also mentioned the efforts by other research groups to utilize alternative genetic packaging, or “vectors,” that are larger and can deliver the actual SCN1A gene to cells. Dr. McTague went on to review how researchers, such as Dr. Vania Broccoli, are co-opting the CRISPR/dCas9 technology in new ways to increase expression of the SCN1A gene as well. It is impossible to discuss the excitement of these novel therapies without also acknowledging the challenges that still exist, including our lack of understanding on windows of opportunity to deliver these therapies and still meaningfully impact patient outcomes, as well as the lack of extensive natural history studies in most of the rare DEE populations making outcome measurements difficult.

New approaches in development. Following on the theme of genetic therapies, a talk by Dr. Ana Ricobaraza at the Investigators Workshop: Beyond Seizures reported a gene therapy approach using an adenovirus vector that is large enough to contain the SCN1A gene. They have been testing the approach in a mouse model of Dravet syndrome, and while there are still many hurdles to address, they are seeing benefits for seizure reduction, even when the therapy is given several weeks after seizures begin in this mouse model.

Encoded Therapeutics: ETX101. A poster presented the details of delivery and safety of ETX101, the therapy being developed by Encoded Therapeutics in non-human primates. Their approach uses an AAV-9 vector containing an engineered DNA-binding protein that can increase SCN1A gene expression specifically in GABAergic interneurons. When the vector was delivered directly to the brain of healthy primates by intracerebroventricular (ICV) injection, there was broad delivery throughout the brain and it was well-tolerated. Encoded is working to bring this therapy to human clinical trials in the near future.

  • Belle, et al. “ETX101, a GABAergic Interneuron Selective AAV-mediated Gene Therapy for the Treatment of SCN1A+ Dravet Syndrome: Biodistribution and Safety in Non-human Primates.” AES 2020, Abstract 391.

Stoke Therapeutics, STK-001. Two poster presentations were related to the new antisense oligonucleotide (ASO) therapy being developed by Stoke Therapeutics, called STK-001. This therapy targets SCN1A gene expression at the RNA level, increasing expression of the healthy Nav1.1 sodium channel. Previous publications have detailed the development of this approach and efficacy of STK-001  in mouse models. Now that this therapy has entered human clinical trials, there was a poster detailing the current study design. The study includes 2 arms, a single dose arm (one injection of 10, 20, or 30mg) or a repeated dose arm (one injection of 10, 20, or 30mg every 4 weeks for a total of 3 injections). The trial consists of a 4-week observation period, a dosing period, and a 6-month follow-up. Patients may have the opportunity to continue in an open-label extension study if they meet all the criteria for continued inclusion. While no results from the actual study were presented, we are hopeful to learn more about the initial trial patient results in 2021. In addition to this review of the study design, another basic science poster described the first investigation of this therapy in specific neuronal populations in a Dravet syndrome mouse model, and they reported a restoration of neuronal firing rates to control animal levels, as well as a confirmation of the previously reported reduction in seizure activity in these mice.

  • Laux et al. “Safety and Pharmacokinetics of Antisense Oligonucleotide STK-001 in Children and Adolescents with Dravet Syndrome: Single Ascending Dose Design for the Open-Label Phase 1/2a MONARCH Study.” AES 2020. Abstract 344
  • Wengert et al. “Targeted Augmentation of Nuclear Gene Output (TANGO) of SCN1A Reduces Seizures and Rescues Parvalbumin Positive Interneuron Firing Frequency in a Mouse Model of Dravet Syndrome.” AES 2020. Abstract 236.

Drug and Diet Therapies

New therapies are coming down the research pipeline, entering clinical trials, and hitting the market, and we are still learning new things about treatments that have been around for a long time. Below are updates of several of these therapies from posters presented this year.

Fenfluramine. There were six different posters on this newly FDA-approved therapy for Dravet syndrome that works by modulating the serotonin pathway (in addition to several more talks as well as posters addressing the efficacy of fenfluramine in other seizure disorders). These posters reported the continued measurements of efficacy to reduce seizure frequency in groups of patients with Dravet syndrome between age 2 and 17 (now tested across three separate cohorts of patients total), as well as in patients 18 and over, and an additional report showed the efficacy of fenfluramine continues during long-term use. Other posters detailed the positive impacts reported by families on cognition, motor function, sleep, and disposition as well as improvement on clinician scores of clinical global impression, behavior, cognitive function, and motor ability following use of fenfluramine. Because fenfluramine can cause appetite suppression, a common initial side effect is weight loss. A study looked at this more closely and predicted based on the current data from up to two years of use that fenfluramine does not have long-term effects on growth. Lastly, given the concerns over heart health from the history of fenfluramine as an active ingredient in weight-loss drugs for obesity, none of these studies of fenfluramine in Dravet syndrome have identified any serious cardiac issues, supporting that fenfluramine is safe in this population at the currently indicated dosages.

  • Miller et al. “Efficacy and Tolerability With FINTEPLA (Fenfluramine) in Adult Patients With Dravet Syndrome: A Case Series of Patients Participating in Phase 3 Studies.” AES 2020. Abstract 849.
  • Sullivan et al. “Fenfluramine (FINTEPLA) in Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial (Study 3).” AES 2020. Abstract 853.
  • Scheffer et al. “Efficacy and Tolerability of Adjunctive FINTEPLA (Fenfluramine Hydrochloride) in an Open-Label Extension Study of Dravet Syndrome Patients Treated for Up to 3 Years.” AES 2020. Abstract 978.
  • Jensen et al. “The long-term effects of Fenfluramine on patients with Dravet syndrome and their families: A qualitative analysis.” AES 2020. Abstract 418.
  • Perry. “Fenfluramine (FINTEPLA) provides comparable clinical benefit in adults and children with Dravet syndrome: Real-world experience from the US Early Access Program.” AES 2020. Abstract 1057.
  • Gil-Nagel et al . “Treatment With FINTEPLA (Fenfluramine) in Patients With Dravet Syndrome Has No Long-Term Effect on Weight and Growth.” AES 2020. Abstract 977.

Soticlestat. Soticlestat, or TAK-935/OV935 is a novel therapeutic approach for seizures that targets the cholesterol pathway that was developed through a partnership with Takeda and Ovid Therapeutics and is currently in clinical trials for Dravet syndrome. A poster presentation continued to report the positive results for soticlestat to lower seizure frequency in Dravet syndrome, as well as some trending efficacy for Lennox-Gastaut syndrome as well. The current study also reports that soticlestat treatment is safe and well-tolerated by patients.

  • Hahn et al. “Efficacy, safety and tolerability of soticlestat (TAK-935/OV935) as adjunctive therapy in pediatric patients with Dravet syndrome and Lennox Gastaut syndrome (ELEKTRA).” AES 2020. Abstract 851.

Cannabidiol (CBD). CBD has been FDA-approved for Dravet syndrome since 2018, but researchers are still working to understand how effective it is for seizure control across disorders and what the molecular mechanisms are that contribute to the seizure reduction seen with CBD. Studies continue to expand on the indication in Dravet syndrome and report the efficacy of CBD to reduce seizures in all patients with refractory epilepsy. Additionally, scientists are using mouse models to identify specific genes and molecules that are affected by CBD to better understand how CBD works and assess if more targeted therapies could be developed from that knowledge.

  • Krishnakumar et al. “Cannabidiol in Refractory Epilepsy: A Single-Center Experience.” AES 2020. Abstract 91.
  • Mora et al. “Quality Improvement Study in Patients with Epilepsy in Treatment with Epidiolex at MUSC Epilepsy Clinic.” AES 2020. Abstract 572.
  • Anderson et al. “Pharmacological validation of endocannabinoid system deficits observed in the Scn1a+/- mouse model of Dravet syndrome.” AES 2020. Abstract 1070.
  • Satpute et al. “Heterozygous deletion of Trpv1 reduces the severity but not the frequency of spontaneous seizures in a Scn1a+/- model of Dravet syndrome.” AES 2020. Abstract 224.

Stiripentol. This relatively new therapy for Dravet syndrome in the US (although utilized for many years in Europe) acts by modulating GABA-A receptor activity. A study of 38 patients with Dravet syndrome within a larger group of patients with epilepsy indicated that those with Dravet syndrome respond most robustly to stiripentol (66% of patients had a 50% or greater reduction in seizure frequency), and  many (41%) remained responders at follow-up.

Another study sought to assess the efficacy of stiripentol to reduce absence seizures using rodent models. Stiripentol treatment reduced the number and duration of absence seizures in both models and the researchers revealed modulation of calcium channels as a novel mechanism of action for stiripentol. Although continued studies are needed to understand how this translates to humans, these results suggest stiripentol may be effective at reducing absence seizure activity.

Lastly, there was another poster detailing recently published results from Dr. Andrade’s group about the risk of hyperammonemia in adults when beginning stiripentol. The researchers stress the importance of monitoring ammonia and carnitine levels closely in this population. Carnitine supplementation allowed patients to effectively remain on stiripentol and achieve seizure reduction, but dose levels needed to be significantly lower than in children. The stiripentol study is published here.

  • Doccini et al. “Long-Term Effectiveness of Stiripentol as add-on therapy in children, adolescents and young adults with different types of refractory epilepsies: a study on 193 patients.” AES 2020. Abstract 93.
  • Riban et al. “Stiripentol inhibits absence seizures in two animal models: Involvement of T-type calcium channels?” AES 2020. Abstract 331.
  • Zulfiqar et al. “ Starting Stiripentol in Adults with Dravet Syndrome? Watch for Ammonia and Carnitine.” AES 2020. Abstract 140.

Ketogenic Diet. With so many new therapeutic options entering the field for Dravet syndrome, it is important to remember that the ketogenic diet still remains a top consideration for the treatment of Dravet syndrome. A recent study at Children’s Hospital of Philadelphia underlined the long-term efficacy of the ketogenic diet as a treatment option with 25% of patients achieving a 50% or greater reduction in seizure frequency after 1 year and 44% of patients experiencing seizure-free periods with a median length of 8.5 months. The researchers underlined the importance of the managing medical center providing supportive services to families implementing the diet for long term success.

  • Worden. “Long-term success and retention of children with Dravet Syndrome on the ketogenic diet.” AES 2020. Abstract 1016.

Novel drug therapies. A novel therapeutic being developed by Xenon Pharmaceuticals called XPC-8770 specifically targets the Nav1.1 sodium channel that is encoded by the SCN1A gene. Dravet syndrome is a haploinsufficiency, meaning the SCN1A gene does not make enough Nav1.1 sodium channels, leading to decreased sodium signaling in the inhibitory neurons that usually express and use the Nav1.1 channel. XPC-8770 can increase the activity of the Nav1.1. channels that do get made in Dravet syndrome, and in a mouse model of Dravet syndrome, XPC-8770 does just that by improving the firing of the affected inhibitory neurons and suppressing induced seizures. In theory, outside of a genetic approach, this comes closest to modifying the direct cause of Dravet syndrome, and it will be exciting to watch as research continues on this approach.

  • Goodchild et al. “Selective Potentiation of Inhibitory Networks Prevents Seizures in a Mouse Model of Dravet Syndrome.” AES 2020. Abstract 861.

Given the particularly robust response of Dravet syndrome to the ketogenic diet, researchers have turned to glucose metabolism as a potential modifier of disease in Dravet syndrome. Dr. Banerji, a previous DSF post-doctoral fellowship recipient, gave a presentation at the Research Roundtable and presented a poster at AES detailing the discovery of a modulator of the gluconeogenesis pathway that can normalize metabolism and suppress seizures in a zebrafish model of Dravet syndrome. Further research is needed, but this pathway could represent a novel therapeutic target for Dravet syndrome.

  • Banerji et al. “Enhancing glucose metabolism via gluconeogenesis is therapeutic in a zebrafish model of a Dravet syndrome.” AES 2020. Abstract 648.

SUDEP

Sudden Unexplained Death in Epilepsy, or SUDEP, received a lot of well-deserved attention at the AES conference this year. One of my biggest takeaways on the subject of SUDEP from the meeting, was that we need to talk about SUDEP risk more than we are- patients and advocacy groups need to talk about how it impacts families, clinicians need to educate families on the risks, and researchers need to keep working to understand the causes and ways to prevent it. Next week’s blog post will review the Partners Against Mortality in Epilepsy (PAME) symposium that focuses heavily on mortality risks in epilepsy and SUDEP, but I wanted to highlight a few other areas of the meeting that also mentioned SUDEP research.

As SUDEP often occurs at nighttime and/or in sleep, there was an entire session dedicated to our understanding the night-time contributors to seizure-associated death. Dr. Judy Liu discussed how genes that contribute to regulation of circadian rhythms, or daily patterns of behavior and body regulation, are often dysregulated in refractory epilepsy. In fact, when these same circadian rhythm genes are disrupted in mice, it can cause seizures that develop during sleep. Dr. Benton Purnell followed up by discussing mouse models of epilepsy that are at greater risk of seizure-induced death during the night. Dr. Purnell nicely referenced a previous study by Sanchez et al (2019, Sleep DOI: 10.1093/sleep/zsz173) that described disrupted sleep and altered circadian rhythms in a mouse model of Dravet syndrome. It is difficult at this stage to draw strong translations from these studies, but taken together, they highlight that the circadian pattern of behavior and sleep play an integral role in epilepsy and research is uncovering molecules and pathways that perhaps can be targeted in the future to improve sleep, reduce seizures, and prevent SUDEP.

In addition to these studies of circadian effects on the risk for SUDEP, there were also several poster presentations focused on revealing the signaling networks in the brain that contribute to SUDEP risk, particularly centers of the brain that regulate breathing and the heart. Researchers specifically focused on impaired signaling in the brain stem and how inflammation and neuronal support cells may play a roll.

  • Xi et al. “Characterizing Factors Contributing to BNST Excitation During Seizures in a Dravet Syndrome Mouse Model.” AES 2020. Abstract 20.
  • Goh et al. “Evaluation of potential mechanisms of SUDEP in a mouse model of Dravet syndrome.” AES 2020. Abstract 21.
  • Yuan et al. (446) “Altered excitability of the brainstem vagus nerve dorsal motor nucleus in the Scn1b null mouse model of Dravet Syndrome.” AES 2020. Abstract 446.
  • Teran et al. “Scn8a N1768D/+ mice show impaired inter-ictal CO2 chemoreception and seizure-induced death due to central apnea.” AES 2020. Abstract 659.

Adults with Dravet Syndrome

Despite all the progress in research, there is still a lack of knowledge surrounding Dravet syndrome in adults. Thankfully, some studies are beginning to focus on adults. Dr. Danielle Andrade is one of the leading experts on Dravet syndrome in adults and has been collaborating on projects to increase our understanding of the presentation of symptoms and treatment as patients age. During the DSF Research Roundtable, Dr. Andrade discussed an ongoing project to characterize behavior and gait in adult with Dravet, and the behavioral data was also presented as a poster. The study population is still small, but this initial characterization will hopefully lead to better recommendations for treatment approaches. Related to treatment approaches, there was another poster detailing recently published results from Dr. Andrade’s group about the risk of hyperammonemia in adults when beginning stiripentol. While this is mentioned in the stiripentol section above, I felt it was important enough to include under both sections of the post. The researchers stress the importance of monitoring ammonia and carnitine levels closely in adult patients starting stiripentol therapy. Carnitine supplementation allowed adult patients to effectively remain on stiripentol and achieve seizure reduction, but dose levels needed to be significantly lower than in children. The stiripentol study is published here.

  • Selvaraiah et al. (167) “Adaptive Behaviour and Skill Changes in Adult Patients with Dravet Syndrome.” AES 2020. Abstract 167.
  • Zulfiqar et al. “ Starting Stiripentol in Adults with Dravet Syndrome? Watch for Ammonia and Carnitine.” AES 2020. Abstract 140.

Neuronal Communication

There are continued efforts to understand the underlying mechanisms of seizures and dysfunctional brain communication in Dravet syndrome. Dr. Ethan Goldberg and Dr. Jessica Chancey gave talks at the Research Roundtable, as well as presented posters from their labs at the AES meeting, describing some of the neuronal communication that is disrupted in two different mouse models of Dravet syndrome. In the SCN1A model of Dravet syndrome, there is a developmental component to the circuit disfunction of neurons, and their group has identified that there is not only loss of inhibition, but also an independent excess of synaptic excitation. Dr. Chancey described how altered synaptic plasticity may underlie the cognitive deficits in an SCN1B mouse model of Dravet syndrome. Finally, another poster looking again at the SCN1A mouse model of Dravet syndrome identified that suppressed signaling in the hippocampus following seizure activity may be responsible for post-ictal memory impairment.

  • Mattis et al. “Cortico-hippocampal circuit dysfunction in a mouse model of Dravet syndrome.” AES 2020. Abstract 5.
  • Chancey et al. “Altered excitability, synaptic properties, and plasticity in the Scn1b knockout mouse model of Dravet syndrome.” AES 2020. Abstract 217.
  • Beckman et al. “Elevated temperature and interictal activity modulate hippocampal sharp-wave ripples in a mouse model of genetic epilepsy.” AES 2020. Abstract 221

Dravet Syndrome and Comorbidities

A poster presented the initial results of the BUTTERFLY observation study run by Stoke Therapeutics to understand non-seizure outcomes in Dravet syndrome. The study goes on to describe the key findings of impacts on cognition that are generally absence in pre-school but emerge as significant by school-age. However, the researchers noted the large variability in this among patients in the study. While many of the studied cognitive and behavioral domains did appear to have significant gaps that widened with age, language skills appeared to continue to develop over time, and some patients showed improvement across many of the domains, again highlighting the variability in presentation.

  • Sullivan et al. “Observational Study to Investigate Cognition and Other Non-seizure Comorbidities in Children and Adolescents with Dravet Syndrome: Patient Analysis of the BUTTERFLY Study.” AES 2020. Abstract 81.