MaRS Innovation is partnering with Dr. James Eubanks at the University Health Network (UHN) to develop a new treatment for Rett syndrome, a rare developmental disorder found almost exclusively in girls and women.
Infants with Rett syndrome develop and grow normally until the age of 8 to 12 months when symptoms begin appearing. Although the symptoms vary in type and severity, most of the girls and women with the disorder cannot speak or use their hands purposefully. Many also experience seizures that are difficult to control with medications. Presently, there is no cure for Rett syndrome, and the available treatments can only help alleviate symptoms.
Researchers have known for many years that most cases of Rett syndrome are caused by mutations in the MECP2 gene; however, the mechanisms that link these genetic changes to the syndrome’s diverse symptoms are not well understood.
“We believe that we have discovered an important piece of the puzzle,” says Dr. Eubanks, a Senior Scientist at the Krembil Research Institute (UHN) who has been studying the disorder for over 20 years.
MaRS Innovation will initially invest up to $400,000 to help translate Dr. Eubanks’ discovery into a new treatment for Rett syndrome. The funds will support the creation and evaluation of drug-like compounds that target TRPM2, dampening its activity, in the brain of Rett patients. Dr. Mark Reed, a medicinal chemist and head of Krembil’s Centre for Medicinal Chemistry and Drug Discovery, will oversee the work, which will be split between the Centre and the Charles River Discovery site in the United Kingdom. The new partnership will also give Drs. Eubanks and Reed access to MaRS Innovation commercialization services to support further development of any promising treatments.
Dr. Tore Eid’s CURE-funded research aims to understand how gut bacteria can impact seizure development, inflammation, and neurodegeneration.
The team found increased levels of certain amino acids, potentially made by gut bacteria, in the epileptic brain regions of individuals with focal epilepsies.
Short-term treatment with these amino acids reduced spontaneous seizures in a rat model of epilepsy, while a long-term treatment worsened seizure frequency.
Dr. Eid’s studies have the potential to develop epilepsy treatments such as dietary interventions and other safe manipulations of gut bacteria.
CURE grantee, Dr. Tore Eid, and his team at Yale University, are conducting exciting research to understand how gut bacteria can influence the development and manifestation of seizures. This impactful work, funded by the Heldman-Kirshner family grant in honor of Alex Heldman, could lead to simpler and safer treatments for epilepsy.
Over 500 different types of bacteria live in our gut alone.1 This dense collection of bacteria, called gut microbiota, helps us digest food, provides important nutrients, builds immunity, and protects us from harmful pathogens. Disruptions to the gut microbiota play a role in many diseases including irritable bowel disease, colitis, and diabetes. There is also evidence that gut microbiota problems are linked to anxiety, depression, and autism spectrum disorders.2 How and whether these bacteria influence epilepsy development and progression is not very well studied. There is some evidence that the ketogenic diet, which is effective in reducing seizure frequency in a number of different epilepsies, may work by modifying the gut microbiota.3
To better understand the role gut bacteria may play in epilepsy, Dr. Eid and his team analyzed brain fluid samples from people with focal epilepsy. They found that epileptic brain regions had increased levels of certain amino acids called branched chain amino acids, which can be made by gut bacteria. Levels of some of these branched amino acids increased in the brain three hours before a spontaneous seizure occurred, while levels of other branched amino acids increased an hour before. This may indicate that there is a “fine-tuning” of these amino acids happening within the body which potentially impacts seizure occurrence.
Next, the team fed these branched chain amino acids to a rat model of epilepsy they developed. A short-term treatment decreased spontaneous seizures while a long-term treatment worsened seizure frequency and caused neuronal loss in an area of the brain called the hippocampus.4 These results provide evidence that molecules derived from gut bacteria can impact brain chemistry and seizure development.
The team is also interested in understanding how bacteria living in the gut can influence epilepsy development and progression in the brain, focusing on a large nerve called the vagus nerve. This nerve allows the brain and the gut to directly communicate with each other. Dr. Eid’s team has developed techniques to selectively stimulate or suppress signaling only through the afferent vagus nerve, which transmits messages from the gut to the brain, without affecting the efferent nerve, which transmits messages from the brain to the gut and other organs.
In future studies, Dr. Eid and his team will perform careful manipulations of gut bacteria in a rat model of epilepsy by feeding the animals specific types of bacteria. The types of bacteria the team plans to use make molecules which can influence brain chemistry and thus potentially affect seizures. The team will study the effect of this treatment along with afferent vagal nerve stimulation/suppression on seizure development, brain inflammation, and neuronal loss in the rats.
These studies have the potential to impact epilepsy treatment through safe manipulations of gut bacteria through, for example, dietary interventions, probiotics, or antibiotics.
1 Eckburg PB et.al. Diversity of the human intestinal microbial flora, Science. 2005 Jun 10;308(5728):1635-8 2 E.Y. Hsiao et.al Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders, Cell. 155 (2013) 1451-1463 3 Olson CA, Vuong HE et. al. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet, Cell. 2018 Jun 14;173(7):1728-1741.e13. doi: 10.1016/j.cell.2018.04.027 4 Gruenbaum SE, Dhaher R et. al., Effects of Branched-Chain Amino Acid Supplementation on Spontaneous Seizures and Neuronal Viability in a Model of Mesial Temporal Lobe Epilepsy, J Neurosurg Anesthesiol. 2019 Apr;31(2):247-256
This research is generously supported by a grant from Jen Scott and Pierre-Gilles Henry, PhD, in honor of Felix Henry.
CURE grantee Dr. Mingshan Xue created mice modeling the features of STXBP1-related epileptic encephalopathy (EE) to explore why not having enough STXBP1 activity can cause epilepsy.
The team found that inhibitory brain signaling was diminished in the models, causing excessive neuronal excitation, seizures, and other neurological features seen in humans with EE.
The long-term goal of the team’s project is to understand the mechanisms that cause EEs and use this knowledge to develop new therapies.
Reduced activity of a gene called STXBP1 is one of the most common causes of epileptic encephalopathy (EE),1a group of severe pediatric epilepsies which includes Ohtahara Syndrome, West Syndrome, and Dravet Syndrome. Patients with EE often have aggressive, treatment-resistant seizures, developmental delays, behavioral deficits, and intellectual disability among other clinical features. There is an urgent need to better understand these syndromes and develop new therapies for them.
CURE grantee Dr. Mingshan Xue and his colleagues at the Baylor College of Medicine created mouse models with reduced STXBP1 activity to study epilepsy associated with this genetic variant. Through extensive testing, they determined these mice accurately represented EE clinical features such as seizures, behavioral, and cognitive deficits.2
For their CURE-funded work, the team used these models to determine how not having enough STXBP1 activity could cause EE. The team previously observed high levels of neuronal excitation in the brains of mice with low STXBP1. Thus, Dr. Xue’s team hypothesized that not having enough STXBP1 must prevent inhibitory neuronal signaling, causing an imbalance between excitation and inhibition in the brain.
To test this, the team recorded the electrical activity of neurons in the model with reduced STXBP1 activity. They found that inhibitory brain signaling was indeed diminished in these mice while excitatory signaling was not affected, resulting in excessive excitation, seizures, and other neurological features of EE. Further testing revealed that mice with reduced STXBP1 activity specifically in inhibitory neurons had higher anxiety, impaired motor skills, and reduced cognitive function – all features that are seen in humans with EE.
EEs are typically hard to treat with currently available options. The team’s long-term goal is to understand the mechanisms that cause EEs and use this knowledge to develop new therapies. Since completing their CURE-funded grant, Dr. Xue and his co-investigator have received a National Institutes of Health grant, as well as an American Epilepsy Society postdoctoral fellowship to continue this important work.
Bridging the Gap Between STXBP1 Researchers and Families
We are honored to sponsor and attend the first ever STXBP1 Investigators and Family Meeting (SIFM) on June 21, 2019 and June 22, 2019 in Philadelphia. This conference is hosted by STXBP1 Foundation and the Center for Cellular and Molecular Therapeutics (CCMT).
The need for developing community and driving more research on this group of EEs is clear. The inaugural SIFM will bring together researchers and families of individuals with STXBP1 encephalopathies to foster community development and accelerate the search for a cure. This conference is designed to encourage interaction and in-depth discussions among researchers and clinicians to further research and innovation in this field.
You can find out more information about this conference here.
When the body detects high carbon dioxide (CO2) levels in the blood, a condition known as hypercapnia, it responds by moving more air through the lungs. This increased ventilation helps remove the excess CO2. Research by CURE grantee Dr. Rup K. Sainju and his team at the University of Iowa shows that this response may be weakened in some people with drug-resistant epilepsy, which puts them at an increased risk for severe breathing abnormalities and Sudden Unexpected Death in Epilepsy (SUDEP) following a generalized convulsive seizure.
For their CURE-funded project, Dr. Sainju’s team conducted a study in adults with drug-resistant epilepsy who were admitted to the epilepsy monitoring unit (EMU) at the University of Iowa. In addition to comprehensive heart and breathing monitoring, the team measured the hypercapnic ventilatory response (HCVR) in each patient.1,2 The HCVR measurement evaluates how the body responds to increased blood CO2levels. A low HCVR indicates a poor or weakened ability to remove CO2 from the body.
The study found that patients who had a low HCVR were more likely to have severe breathing abnormalities and a longer period of high, potentially dangerous CO2 levels in the blood after a generalized convulsive seizure. Long-term follow-up revealed one of the patients in the study with the third lowest HCVR passed away of SUDEP 11 months after the study.2
Importantly, this is the first time HCVR has ever been studied in patients with epilepsy. The team demonstrated that an HCVR measurement can be conducted in the EMU rapidly and safely.2 The team also reported that the HCVR measurement was well tolerated by the patients.2
Building on their work, Dr. Sainju’s team also conducted a CURE-funded pilot study to determine if the drug fluoxetine, more commonly known as Prozac, could increase HCVR and reduce seizure-related breathing abnormalities. Fluoxetine increases the availability of serotonin in the brain and there is evidence that the serotonin system increases ventilation in response to hypercapnia. Drugs similar to fluoxetine have been safely tested in mice and humans and shown to increase HCVR. The team hypothesized that giving fluoxetine to patients who have a low HCVR would improve the body’s ability to sense high CO2 levels and reduce post-seizure breathing abnormalities. The team has finished this study, which shows that patients completed it with good adherence. We are eager to see their final analysis.
Dr. Sainju’s study suggests that HCVR is a key measurement which may be useful in predicting the risk of breathing abnormalities and SUDEP. It can be easily and rapidly performed in the EMU with minimal discomfort to people with epilepsy. Future studies will build on this work, analyzing the usefulness of HCVR as a biomarker for SUDEP. Having demonstrated the feasibility of a randomized trial of fluoxetine versus placebo to improve HCVR, the team plans to continue studying fluoxetine and other therapeutic targets.
1 Gehlbach BK et. al. Tolerability of a comprehensive cardiorespiratory monitoring protocol in an epilepsy monitoring unit. Epilepsy Behav. 2018 Aug;85:173-176. 2 Sainju R.K. et. al. Ventilatory response to CO2 in patients with epilepsy. Epilepsia. 2019 Mar;60(3):508-517. 3 Hodges MR, Richerson GB. Medullary serotonin neurons and their roles in central respiratory chemoreception. Respir Physiol Neurobiol. 2010 Oct 31;173(3):256-63.
CURE-funded researchers are using a novel technique to discover ways to predict patients at an increased risk of Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Lori Isom, her team, and co-investigator Dr. Jack Parent at the University of Michigan are transforming skin cells from patients with developmental and epileptic encephalopathy (DEE) syndromes into induced pluripotent stem cells (iPSCs). The team then generates cardiac cells from the iPSCs which retain the patients’ exact genetic information. These unique, patient-specific cardiac cells are used as models to understand if DEE-associated genes play a role in causing heart abnormalities which may lead to SUDEP. The team also hopes to develop measurable indicators, known as biomarkers, of SUDEP risk.
Severe DEE syndromes, such as Dravet syndrome, are associated with a high incidence of SUDEP. It is estimated that up to 20% of patients with Dravet syndrome die from SUDEP.1 There is still much to be understood about the mechanisms of SUDEP and how to predict who is at risk for it.
Dravet syndrome and other DEEs are often associated with variants in genes, such as SCN1A, SCN1B, and SCN8A. These genes provide instructions to make sodium ion channels, which are very important proteins that help brain cells transmit electrical signals. The same genes are also expressed in the heart; thus, the team hypothesizes that any variants in these genes that disrupt electrical signaling in the brain would affect normal electrical function of the heart as well. In support of this hypothesis, the investigators’ previous work in mouse models of Dravet syndrome and DEEs showed that these mice exhibited irregular heartbeat, which in some cases preceded SUDEP-like events.2-4
In this CURE-funded project, the investigators expanded upon their previous work by testing their hypothesis in heart muscle cells called cardiac myocytes, generated in the laboratory from skin cells of patients with Dravet syndrome or other DEEs using iPSC technology. This Nobel Prize-winning technology involves obtaining skin or blood cells from patients and converting them to iPSCs. These are stem cells that can be converted into almost any specialized cell type in the body, such as heart, muscle, pancreatic, or neuronal cells. The cells are patient-specific, meaning they retain the unique genetic make-up of the patient they originated from, allowing investigators to study cell types which would otherwise be very difficult or impossible to obtain from a living patient.
Dr. Isom, Dr. Parent, and their colleagues previously used iPSC technology to generate heart muscle cells from four patients with variants in the SCN1A gene and found increased sodium currents and spontaneous contraction rates in these cells, suggesting cardiac electrical dysfunction.5 Cardiac abnormalities were subsequently found in the patient with the highest increase in sodium current.5 These data suggest that iPSC-cardiac cells may be useful models for identifying and developing biomarkers, such as increased sodium current, as indicators of SUDEP risk.
The investigators used the same technique to study variants in the SCN1B and SCN8A genes. The team observed that iPSC-cardiac myocytes derived from a patient with SCN1B Dravet syndrome had increased sodium currents similar to those seen in iPSC-cardiac myocytes from the patient with SCN1A Dravet syndrome, suggesting that variants in these two different genes could cause heart abnormalities through similar mechanisms. Preliminary data in iPSC-cardiac myocytes from patients with DEE caused by variants in SCN8A, suggest that these cells have altered beating rates but no change in sodium current, which is aligned with their observations in a mouse model with a variant in SCN8A.
Taken together, these results reveal mechanisms by which different epilepsy-related genes can affect heart function and SUDEP. Future research will investigate the impact of variants of a specific non-ion channel gene to see if it causes altered cardiac beating. Patient-specific iPSC cardiac myocytes are a very useful model to study SUDEP mechanisms and could be developed as diagnostic biomarkers to identify SUDEP risk in patients.
1 Cooper MS et al. Mortality in Dravet Syndrome. Epilepsy Res. 2016 Dec; 128:43-47. 2 Auerbach DS et al. Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome. PLoS One. 2013;8(10). 3 Lopez-Santiago LF et al. Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals. J Mol Cell Cardiol. 2007;43(5):636-47. 4 Frasier CR et al. Cardiac arrhythmia in a mouse model of SCN8A Epileptic Encephalopathy. Proc Natl Acad Sci U S A. 2016; in press. 5 Frasier CR et al. Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient Derived Cardiac Myocytes. Stem Cell Reports. 2018 Sep 11;11(3):626-634.
This grant is generously supported by the Isaiah Stone Foundation.
A potential link between epilepsy- and SUDEP-associated SCN1A gene variants and Sudden Infant Death Syndrome (SIDS) has been discovered by CURE Grantee Dr. Annapurna Poduri of Boston Children’s Hospital.1 Her work, generously supported by the Isaiah Stone Foundation, may provide insight into SIDS and support genetic evaluation focused on epilepsy genes in SIDS. In Dr. Poduri’s analysis of 10 infants who died of SIDS, two children were found to have disease-associated variants in the SCN1A gene. Despite finding variants in an epilepsy-related gene and hippocampal lesions that are commonly associated with temporal lobe epilepsy, these children had no history of seizures or epilepsy.
SIDS occurs when a seemingly healthy baby dies suddenly. The sudden death of a child is a tragic occurrence and even more distressing when there is no known cause. There are several categories of this type of death: SIDS if the child is less than one year old; Sudden Unexplained Death in Childhood (SUDC) if the child is greater than one year old; and Sudden Unexpected Death in Epilepsy (SUDEP) if the child has epilepsy.
These types of childhood death are traditionally thought of as separate entities and the causes behind them are largely unknown. However, by finding a link between SIDS and SCN1A mutations,2,3 Dr. Poduri and her colleagues have deepened our understanding of the potential genetic factors behind sudden death in children. This research also suggests epilepsy genes may be more widely important in cases of sudden death in children than originally thought.
In fact, as an integral part of her CURE-funded work, Dr. Poduri and her colleagues in Robert’s Program on Sudden Death in Childhood set out to understand the genetic basis of these sudden childhood deaths, with the hypothesis that there may be a common mechanism between some cases of SIDS, SUDC, SUDEP, and epilepsy. This hypothesis is based on neuropathological abnormalities seen in the hippocampal region of approximately 40% of cases with SIDS and SUDC.4
Although typically considered rare, more children die each year from Sudden Unexplained Death in Pediatrics (SUDP), a category that includes SIDS and SUDC, than from childhood cancer or heart disease.5 Understanding the reasons behind these types of death is important in understanding how to prevent them.
Besides finding variants in the SCN1A gene in two children who died of SIDS, Dr. Poduri and her colleagues also found variants in the epilepsy-related SCN1B gene in two siblings who died suddenly and unexpectedly.6 These important findings identify additional epilepsy-related genes which may underlie some cases of sudden death in children, supporting the team’s idea that there are shared mechanisms between SIDS, SUDC, and epilepsy.
In the future, Dr. Poduri and her colleagues plan to continue their analysis of potential epilepsy-associated genetic variants, which may contribute to sudden childhood death, to better understand causes of these devastating occurrences. They are hopeful their findings will apply to children with and without epilepsy who may be at risk for sudden death. Their overall goal is to identify not only genetic risk factors for SIDS and SUDC, but also other means of identifying children at risk for sudden death. This work could lay the foundation for strategies which can be systematically implemented to prevent these deaths from occurring.
1 Brownstein CA et al. SCN1A variants associated with sudden infant death syndrome. Epilepsia 2018; 59(4):e56-e62. 2 Escayg A and Golding AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia 2010; 51(9):1650-1658. 3 Goldman AM. Mechanisms of sudden unexpected death in epilepsy. Curr Opin Neurol 2015; 28(2):166-174. 4 Kinney HC, Poduri A et al. Hippocampal formation maldevelopment and sudden unexpected death across the pediatric age spectrum. J Neuropathol Exp Neurol 2016. 75(10):981-997. 6 Poduri, unpublished.
A potential method of predicting who will get epilepsy following a brain infection, such as that brought on by malaria, has been discovered. This breakthrough is the result of work by two CURE grantees, Dr. Bruce Gluckman and Dr. Steven Schiff of Pennsylvania State University.
Individuals who contract cerebral malaria (malaria accompanied by a coma, typically spread by mosquitos) are at a substantially increased risk of developing epilepsy.1 Malaria is especially widespread in non-industrialized areas of the world and often affects children.2 Because malaria is so widespread, it may be the most significant cause of post-infection epilepsy in the world today. Currently, there are no methods to predict who will develop epilepsy, or any means of preventing epilepsy after such an infection.
This makes Dr. Gluckman and Dr. Schiff’s discovery so critical. Together with their team members Fatemeh Bahari and Dr. Paddy Sstentongo, they found a combination of brain and heart activity in mice that could accurately predict which animals would develop seizures and epilepsy after infection with malaria.3
Using their CURE grant, Drs. Gluckman and Schiff studied the connection between cerebral malaria and epilepsy by first developing a mouse “model” replicating malaria-induced epilepsy. In addition, they investigated possible ways to determine which mice would go on to develop epilepsy after infection.
Using the mice which developed epilepsy after infection with malaria, the research team measured two important variables often associated with epilepsy: the activity of the brain and heart. They found abnormal brain activity immediately followed by abnormal heart activity – but only in the animals which went on to develop epilepsy.
This discovery represents a possible biomarker for predicting epilepsy following infection with malaria. In other words, these may be measurable indicators to determine the infected individuals who will develop epilepsy. Furthermore, the abnormal brain and heart activity was detectable as early as 14 weeks before the first seizure, opening a potential window during which therapeutic interventions might be used to prevent epilepsy.
Drs. Gluckman and Schiff plan to continue this work, using these findings to develop treatment methods for people who contract cerebral malaria to prevent them from developing epilepsy. They are hopeful their discovery will lead to a means to eliminate not only post-malarial epilepsy, but also epilepsy caused by other types of brain injuries.
A less invasive yet more accurate, safe, and effective method of recording seizures from deep layers of the brain may now be possible, thanks to the work of CURE grantee Dr. Flavia Vitale.1
Dr. Vitale, of the University of Pennsylvania, and a team of researchers engineered a method of delivering thin, ultraflexible electrodes deep into neural tissue. The way these electrodes are constructed and inserted limits the brain damage associated with the penetrating electrodes currently used for recording neural signals. This new and improved technology may allow researchers and clinicians to better pinpoint changes in electrical activity in the brains of people with epilepsy.
Recording this electrical activity is essential to understanding the epileptic “map” of a person’s brain. Understanding the map helps doctors locate where seizures originate (the focus) and learn how they spread. With this information, doctors can more effectively treat epilepsy. Knowing the focus of an individual’s epilepsy can, for example, help guide epilepsy surgery or the implantation of an anti-seizure device. This kind of precision isn’t always possible with current clinical mapping tools because of their invasiveness and low-resolution, Dr. Vitale notes.
The thinner, softer, and higher-resolution electrodes can be focused, moved, and adjusted after implantation, reaching deep layers of the brain while causing minimal damage. Thus far, the team has successfully tested this system in the small, fresh-water organism called hydra as well as in rats.
Dr. Vitale is now performing new experiments to demonstrate that this updated electrode technology is safer and less damaging than the placement of stiffer, commercial electrodes.
As a next step in her CURE project, Dr. Vitale will also focus on understanding the safety of her electrode system after it has been implanted for a long period of time. By completing the development of this novel recording system, her overall goal is to increase the understanding of brain activity patterns in individuals with epilepsy, improving the safety and accuracy of recordings and the treatment of epilepsy.
1 Vitale F, et al. Fluidic microactuation of flexible electrodes for neural recording. Nano Lett 2018; 18(1):326-335.
Relatively small changes in environmental factors which improve the ‘internal clock’ (otherwise known as the circadian rhythm) and the quality of sleep lead to decreases in seizures in mice with similarities to Dravet syndrome, a severe form of epilepsy. These promising results are the latest findings from the lab of CURE grantee Dr. Franck Kalume of Seattle Children’s Hospital, whose grant is generously supported through the BAND Foundation.
Individuals with Dravet syndrome have problems with their circadian rhythm and with regulating their sleep.1 Upon observing that mice with similarities to Dravet syndrome have similar sleep disturbances,2 Dr. Kalume and his team set out to determine if improving circadian rhythm and sleep patterns in these mice could reduce the occurrence of seizures.
To improve circadian rhythm in the mice, the team confined either meals or exercise to nighttime, when mice are typically active. The team limited these activities during the day, when mice typically sleep. As a result of these simple changes, the team found that the mice became more active at night and less active during the day, an indication of improved circadian rhythm. The mice also showed improvements in the quality of their sleep.
Significantly, restricting these activities to nighttime led to a decrease in the incidence of irregular brain activity that is characteristic of an epileptic brain, an indication that improvements in sleep practices may improve epilepsy.
Dr. Kalume and his team next plan to confine both exercise and meals to nighttime to see if this leads to an even greater reduction of seizures. They also plan to determine the effect of these changes on the risk of sudden death in these mice, as these mice and humans with Dravet syndrome are more susceptible to Sudden Unexpected Death in Epilepsy (SUDEP).
These important results contribute to our understanding of the relationship between sleep and epilepsy and provide hope for the development of new therapies to improve epilepsy outcomes. Dr. Kalume and his team hope these studies will lead to practical steps not involving medication that individuals with epilepsy can take to improve their circadian rhythm and sleep to reduce seizures and the risk of SUDEP.
1 Licheni SH et al. Sleep problems in Dravet syndrome: a modifiable comorbidity. Dev Med Child Neurol 2018; 60(2):192-198. 2 Kalume F et al. Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome. Neurobiol Dis. 2015; 77: 141-54.
A new treatment for Dravet syndrome, a rare and catastrophic form of drug-resistant epilepsy, may soon be on the horizon thanks to the work of CURE grantees Dr. Glenn King of the University of Queensland and Dr. Steven Petrou of the Florey Institute of Neuroscience and Mental Health. Drs. King and Petrou identified a peptide found in spider venom which can reduce seizures and mortality in mice modeling the symptoms of human Dravet syndrome.1
The majority of Dravet syndrome cases are caused by mutations in a gene that lead to too little inhibition and too much excitation in the brain, triggering the hyperexcitability seen with seizures.2,3 Drs. King and Petrou found that the spider venom peptide works to restore the balance of inhibition and excitation in the brains of Dravet syndrome mice, decreasing hyperexcitability and reducing seizures. Furthermore, the team found that this peptide also decreases mortality in these mice.
Drs. King and Petrou next plan to investigate this peptide’s effects on other symptoms associated with Dravet syndrome, such as anxiety, autistic traits, and sleep disturbance. They will also explore ways to develop this peptide into a treatment for epilepsy, including methods of delivering the peptide into the brain.
Besides providing a potential new treatment for Dravet syndrome, these results are especially important because they highlight the therapeutic power of venomous substances, Dr. King notes. These substances work due to their ability to target the brain and alter its activity. Dr. King is optimistic that venomous substances may also be used in the treatment of types of epilepsy other than Dravet syndrome, as well as other brain disorders.
We at CURE are also hopeful this line of research will open new treatment possibilities for rare and difficult-to-treat epilepsies. As noted by Dr. King, the overall goal of this research is to develop therapeutics that will reverse all symptoms of Dravet syndrome and enable those with the disorder to live normal lives.
1 Richards et al. Selective Nav1.1 activation rescues Dravet syndrome mice from seizures and premature death. PNAS 2018; 115(34):E8077-E8085. 2 Bender et al. SCN1A mutations in Dravet syndrome: Impact of interneuron dysfunction on neural networks and cognitive outcome. Epilepsy Behav 2012; 23(3):177-186. 3 Liautard et al. Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome. Epilepsia 2013; 54(7):1251-1261.
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