It is a continuing trend that research related to Dravet syndrome (DS) has robust representation at the annual American Epilepsy Society (AES) Meeting. DS came up across sessions large and small throughout the meeting, highlighting examples of the advancements in diagnosis, treatment algorithms, preclinical modeling, and novel genetic therapies that are occurring for DS. Notably, there was also an increased focus across all developmental and genetic epilepsies, representing that the epilepsy field is making progress toward translations that will, hopefully, finally move the needle on truly meaningful outcomes for patients and families struggling with some of the highest disease burdens. In addition to the exciting scientific presentations, other measures of progress were also evident in the continued inclusion and collaboration with advocates and patient advocacy groups like Dravet Syndrome Foundation (DSF). DSF held the 14th annual Research Roundtable on the Thursday night prior to AES, announcing our 2023 grant awardees, hearing presentations from previous DSF grantees, and discussing the state of the field of research (read more about the Roundtable in last week’s blog here). DSF’s Executive Director Mary Anne Meskis, was recognized with the Extraordinary Contributions to the Field of Epilepsy Award by the American Epilepsy Society at the annual Hoyer Lecture. So much of the success of DSF has been fostered by Mary Anne’s strong leadership, and it’s clear the role DSF has played in all of the advancements that are occurring in research related to DS. In addition to receiving this honor, Mary Anne also participated in the Partner’s Against Mortality in Epilepsy Meeting sharing how patient advocacy groups like DSF aid in awareness of mortality risks like SUDEP, and also provided the caregiver perspective as a panelist during a session discussing Comprehensive Care in Developmental and Epileptic Encephalopathies. Outside of attending the exciting scientific sessions, DSF staff and board also hosted a booth to facilitate new connections and engaged in meetings with industry partners at various stages of therapeutic development for DS. Full days of meetings were just another example of the interest in improving outcomes for those living with DS and the exciting advancements that the coming years will bring. Genuinely, there were too many mentions of Dravet syndrome and related topics for me to recount everything, but below you can find a selection of scientific highlights from the meeting.
Novel Therapies for DS
- Stoke Therapeutics presented data from their trials in the US and UK of the antisense oligonucleotide therapy, STK-001. STK-001 works by disrupting an alternative splicing event, leading to more productive expression of healthy SCN1A transcripts. They have analyzed data from 72 patients treated with STK-001 since beginning trials in 2020. Data from all dosing levels suggest seizure reductions, but higher, repeated doses (up to 70mg) appear to show the greatest reductions in convulsive seizure frequency. STK-001 has been generally well-tolerated and 90% of patients have transitioned to open-label extension studies. While the numbers of patients that longitudinal data is available for in these extension phases is limited, there have been substantial improvements in measures of cognition and behavior, as well as in clinician- and caregiver-reported changes. STK-001 remains generally well-tolerated with the only treatment emergent adverse event reported in more than 1 patient being CSF protein increases in 24% of patients, although no clinical symptoms have accompanied this increase.
- Researchers at Boston Children’s show evidence that a potassium channel, Kv3.1, is reduced following seizures in a mouse model of DS, and that potentiation of this channel with AUT1 could reduce seizure frequency and duration suggesting Kv3.1 may be a novel target for DS therapies. (Vermudez and McGinty et al AES Poster #1.118)
- Researchers at Seattle Children’s Research Institute and Allen institute of Brain Science presented their novel genetic therapy approach. The SCN1A gene outsizes the current AAV delivery vectors used for genetic-based therapies. These researchers tested if they could split the SCN1A gene into two parts, deliver the two parts in an AAV vector, and then have the gene reconstruct together once delivered to target neurons. They found that indeed, they could deliver the gene in two parts and result in increased expression of the intact Nav1.1 sodium channel. Delivery of the therapy to the brain of postnatal mice in two different models of DS reduced mortality and susceptibility to thermally induced seizures in both models. Notably, they saw improved therapeutic effects when the therapy was targeted to GABAergic interneurons versus to the entire neuronal population (Ryu et al AES Poster #2.480).
- 4-phenylbutyrate (4-PB) has been garnering attention as a potential therapeutic for developmental and epileptic encephalopathies. Researchers as the University of Michigan have recently tested 4-BP in a mouse model of DS, finding 4-BP treatment reduced mortality and susceptibility to induced and spontaneous seizures. Future work will expand the sample sizes to further examine efficacy of 4-BP in this preclinical model of DS (Daddo et al AES Poster #3.484).
- IAMA Therapeutics recently partnered with Psychogenics to test a selective NKCC1 inhibitor, IAMA-6, in a mouse model of DS. Data presented at AES (Savardi et al AES Poster #1.275) suggested the potential for this therapeutic to reduce seizures. While this work was still preliminary and they are adding additional experiments to confirm preclinical efficacy, IAMA is also working towards beginning Phase 1 safety studies for IAMA-6 in healthy adults.
- Xenon Pharmaceuticals presented that their selectic Nav1.1 sodium channel enhancer, XPC-1418, could restore the electrical balance in neurons from DS mice and improve motor performance, perhaps suggesting this could treat both seizure, as evidenced in other mouse models of epilepsy, and non-seizure symptoms (Goodchild et al AES Poster #2.247).
- Longboard Pharmaceutics presented preclinical data for their 5-HT2C superagonist, LP352, to reduce epileptiform activity and behavioral seizure-like events in a zebrafish model of DS with similar results in some other preclinical epilepsy models (Danks et al AES Poster #3.261). LP352 is currently being tested as an add-on antiseizure therapy in a Phase 2 study for developmental and epileptic encephalopathies, including DS.
- TAK-935 (soticlestat) is a selective inhibitor cholestoral 24-hydosylase and is currently in Phase 3 trials for DS. Caregivers to patients that participated in the previous Phase 2 study report that they are overall satisfied with the study medication (68.4%). Caregivers do not report worsening of non-seizure symptoms and among those reporting improvements, communication was most frequently mentioned (Asgharnejad et al AES Poster #1.282).
- Work from Dr. Manisha Patel’s laboratory has focused on metabolic pathways in Dravet syndrome and novel ways to target metabolic pathways with therapeutics. They demonstrated in a poster at AES the effectiveness of TSPO ligands to reduce behavioral seizures in a zebrafish model of DS, a follow-up to their previous work focused on other targets in this pathway that was funded by DSF (Adair et al AES Poster #3.013).
- While fenfluramine is not a new therapy, there is a new phase 3 study to determine if fenfluramine can be used safely and effectively in patients with DS between the ages of 1 and 2 years. A poster (Wheless et al #1.435) detailed the open-label study design that includes a 4-week baseline, and 8-week titration onto the study drug, and then maintenance for up to 44 weeks in the study. More information about the study and participation can be found at orchidstudy.com.
Understanding the Natural History of DS
Studies that can help us understand the precise symptom presentation and progression of DS over time, often referred to as the natural history of a disease, are incredibly important for clinical understanding of DS, characterization of the unmet needs for patients, and as a template with which to compare the effectiveness of future disease-modifying therapies.
Data from observational study, ENVISION, sponsored by Encoded Therapeutics, was presented detailing the cognitive and executive functioning difficulties in children with DS (Wheless et al Poster #1.193), showing that while developmental gains occur in patients under 2, the gap between these domains in DS widens from neurotypical peers with age. Similarly, measures related to motor function in young children (Brunklaus et al Poster #2.121) also showed significant gaps between age matched control averages, although gains could be measured in this young population of patients with DS. Seizure burden remains high across ages despite the use of multiple top-line therapies and, as has been previously characterized, seizure types greatly change with age. Language and communication deficits emerge prior to 2 years of age and plateaus over time, widening the gap between peers as patients age (Scheffer et al AES Poster #3.179) .
Updates from another recent observational study led by Stoke Therapeutics, called the BUTTERFLY study, was also presented at AES. Consistent with the data from ENVISION, this study also found less improvements over time in measures related to communication and motor function than is seen in neurotypical peers. Additionally, this data confirmed that patients in the study did not show improvement in convulsive seizure frequency over a 2-year period despite treatment with the best available anti-seizure medication (Sullivan et al AES Poster #1.233)
There were also several studies focused on bringing attention to the high overall burden of DS on patients and their families, emphasizing that despite new medications there is still a high unmet need for treatment of seizure and non-seizure comorbidities in DS, including studies supported by DSF and other Dravet syndrome patient advocacy groups such as DS-UK and DSF Spain (AES posters #1.229, #1.369, #1.374, #3.449)
Biomarkers of DS
Researchers are working to better understand biomarkers that may be useful to mark progression of symptoms or to test therapeutic benefit of novel interventions. Analysis of EEGs found some differences in sleep EEGs from patients with DS that is likely related to the known disruptions of GABAergic inhibition (Hall et al AES Poster #1.100). Similarly, another investigation of EEG data concluded subtle differences in EEG patterns of patients with DS compared to healthy controls during wakefulness, and detection of markers that correlate with fine motor function (Neuray et al AES Poster #2.489).
Comorbidities in DS
Work from Dr. Moran Rubinsten in a mouse model of DS showed mice with a mutation in SCN1A have disruptions in core body temperature and were less able to adjust body temperature in response to changes in ambient temperatures. Additionally, there were specific deficits in the ability of DS mice to regulate their temperature during sleep phases, which may relate to the sleep disturbances often reported in patients with DS. They were able to restore SCN1A levels in a specific region of the brain that regulates sleep and temperature, and this restoration normalized these temperature deficits in these mice (Rubinstein et al AES Poster #2.077).
Adults with DS
Fasano et al (2014) reported previously that some motor disruptions in adult patients with Dravet syndrome may respond positively to levodopa. A poster from Suzuki et al (#2.237) tested levodopa in 9 patients with DS in a randomized crossover trial. Overall, levodopa improved gait, but appeared to be more effective in younger patients with less severe gait disturbances. These findings, in context with previous work, suggest that starting levodopa at a younger age may have a greater impact on gait.
DSF collaborated with UCB on a survey to better assess the needs of caregivers to adults with rare epilepsy, including adult siblings that are involved or planning to be involved as caregivers to their siblings with rare epilepsy. The survey results exemplified the extensive supportive needs for many of these adults with rare epilepsy and underlined the lack of programs and resources to aid caregivers and families with long-term adult care planning (Andrade et al AES Poster #1.374).
Using Novel Technology to Study DS
A mouse study suggested surprising ways we may be able to detect risk for SUDEP by applying machine learning algorithms to data collected from behavioral monitoring. Insights into the risk for SUDEP could be gained from examining this data prior to the age of seizure onset, and predictions on risk for SUDEP could be made with more than 90% accuracy (Niibori et al AES Poster #2.078). It will be interesting to see if similar algorithms could predict differences in human patients with DS based on typical daily behaviors.
Research at the Children’s Hospital of Philadelphia (CHOP) is utilizing our current knowledge of neurons and brain connectivity to model neuronal circuits using a computer to better understand the dysfunctional communication that occurs in DS. The hope in the future is that this sort of modeling could be used to probe novel mechanisms for intervention or other questions related to circuit function in DS. Ideally, this could generate new hypotheses to test more quickly than traditional methods, ideally leading to more targeted experiments with increased translatability in subsequent cell and animal model studies (Lawlor et al AES Poster #3.010). Another study also was using computer simulation to look at impacts on interneuron signaling from differing types of SCN1A variants, representating loss-of-function and gain-of-function mutations, finding that regardless of the mutation type, there could be a similar impact on network inhibition, leading to seizures (Knox et al AES Poster #3.017).
Another group at CHOP is also using technology in creative ways to improve clinical care. Researchers were able to develop algorithms based on information from healthcare claims to determine features that were more (or less) likely to be found in patients diagnosed with DS. This information could be used to determine patients that were most likely to be diagnosed with DS even before the age of 1 year. Future applications of these types of predictive approaches could decrease the time to diagnosis and help patients access appropriate therapeutics earlier in their medical journey (Parthasarathy et al AES Poster #3.192).
Premature Mortality and SUDEP
Premature mortality is a difficult topic to discuss, and I often find myself quite moved during the annual Partners Against Mortality in Epilepsy (PAME) Meeting. This year was no exception as one of the first speakers was Kelly Cervantes, a passionate write, speaker and advocate, who shared about losing her daughter and the complex emotions surrounding that loss that inspired her recent book, Normal Broken. Premature mortality occurs in 15-20% of patients with DS, most often due to Sudden Unexpected Death in Epilepsy (SUDEP). The PAME meeting and presentations at AES this year exemplified that we are making progress in our understanding of mechanisms and risk factors contributing to SUDEP and other causes of mortality in epilepsy that will hopefully lead to effective interventions.
SUDEP often occurs at night, frequently following an unwitnessed seizure. SUDEP has been incredibly difficult to study, but research suggests suppression of respiration and cardiac function. Several of the talks at PAME focused on the respiratory component, trying to understand the brain regions that may be involved in the suppression of breathing that precedes SUDEP. One example of this came from Dr. Brian Dlouhy whose recent work has identified a very specific site in the brain, within a region called the amygdala, that is involved in suppression of breathing and ‘air hunger.’ Their work found that central apnea is more likely to occur when seizures spread to the amygdala, this can be mimicked by electrical stimulation of this brain site, and apnea can occur even several minutes later. This work could lead to important advancements, including insight into patients that are more at risk for respiratory suppression during or following seizures, and possibly even future treatments that could target this site in the brain.
In DS, there is also increased interest in understanding how mutations in SCN1A impact cardiac function and if that contributes to the increased risk of SUDEP. The sodium channel encoded by the SCN1A gene is important for brain function, but it is also expressed in the heart. The majority of patients do not have obvious changes in cardiac function at baseline, but subtle changes in cardiac function may make a difference when the heart is under more stress, such as during or after a seizure. Researchers have been studying this animal models, cells from patients, and by cardiac monitoring in patients. A previous DSF grant awardee, Dr. David Auerbach has been reviewing long-term cardiac data from patients with DS and Lennox-Gastaut Syndrome (LGS) to understand how heart function differs at baseline and during seizure events (Ryan et al AES poster #3.100). They have been finding differences in heart rate and electrical activity surrounding seizures, and a portion of the cardiac recordings exhibit abnormalities. They are continuing to more closely characterize what abnormalities might be associated with SCN1A mutations and DS which may provide insights into the cardiac risk factors contributing to SUDEP.
In addition to respiratory and cardiac function, some researchers are also investigating why SUDEP more frequently occurs at night. Researchers at the University of Iowa showed in a poster at AES that seizure-related mortality is more likely to occur at night than during the day, despite mice being nocturnal and more active during this period (Kreitlow et al AES Poster #1.066).Circadian rhythm is our ‘internal clock’ that regulates many of the daily cycles in the body across a 24-hour period. There have been a handful of studies suggesting dysregulation of circadian rhythm in DS, which may contribute both to sleep disruptions as well as SUDEP. DSF just awarded a 2023 grant to researchers to look at circadian rhythm markers in patients with DS.
The PAME meeting called out some important points families might consider.
- Prof Helen Cross presented data showing that across all patients with epilepsy, reduced mortality rates are seen for patients seen by a comprehensive epilepsy care program versus a neurologist alone. DSF maintains listings of Comprehensive Care Centers with experience in treating patients with DS and related epilepsies.
- Dr. Elizabeth Doner discussed the common cooccurrence of pneumonia and respiratory conditions in patients with epilepsy and comorbid neurodisability. This can be due to acute aspiration related to seizures or from chronic lung disease due to recurring microaspirations occurring with or without seizures. These are not unfamiliar topics in the DS population. In addition to aspiration with seizures, patients with DS can develop other difficulties with feeding and swallowing that also may contribute to aspiration-related pneumonias; some families consider feeding tubes as an option in these situations.
- Families of patients with epilepsy can advocate ahead of time with local EMS providers to aid in smoother responses to medical emergencies. Preparing a Seizure Action Plan (SAP) ahead of time with the treating neurologist, with special instructions for EMS, is also helpful in having these non-emergency discussions, as well as during an emergency response. DSF also has printable educational brochures that can be used to help educate about the basics of DS since many EMS providers may not have encountered this rare disease.
- Consider seizure monitoring, particularly at night. While SUDEP might not always be preventable, physical stimulation and ensuring the individual has not turned facedown during the seizure may be helpful. You can learn more about some of the available seizure monitoring devices from DannyDid.org, and remember that DSF offers patient assistance grants that can help to cover costs associated with a monitoring device.