Genetics Based Research on Treatment Resistant Epilepsy

 

Andrew Escayg, MD

Dr. Escayg’s research interests lie in understanding the molecular basis of neurological diseases, such as epilepsy and autism. With a recent grant award from the National Institute of Neurological Disorders and Stroke (NINDS), his research focuses on shutting off a gene called SCN8A that can raise the threshold of excitability for neurons, thus lowering susceptibility to seizures. Scientists plan to test a gene-therapy-like technique for shutting off SCN8A in mice, with an eye towards developing similar treatments for humans.  

 

Our lab uses a combination of human and mouse genetics, mouse disease models and genome analysis/bioinformatics in order to determine the molecular basis of inherited neurological disorders. We have a broad interest in neurological disease and the disorders that we are currently working on include epilepsy, movement disorders and migraine. The long-term goal of our research is to develop better diagnostic tools and more effective therapeutic agents.

 

Of particular interest to us is the role of voltage-gated ion channels in disease. Voltage-gated ion channels play a critical role in communication between neurons in the brain and the maintenance of normal nervous system function. Diseases that result from mutations in ion channel genes are called channelopathies. Channelopathies underlie a wide range of disorders that include cardiac and skeletal muscle defects and neurological disorders such as epilepsy.

 

Our research can be divided into a number of different components. 

 

Human disease gene identification

One component of our research involves the identification of genes responsible for inherited human neurological disorders such as epilepsy. We use two experimental approaches. If we suspect that a known gene is mutated in a patient with epilepsy, then the candidate gene can be directly screened for novel mutations. If we suspect that a novel gene may be responsible, then we use a variety of genetic techniques in order to identify the novel disease gene. Using these approaches we have, for example, identified several new mutations in the voltage-gated sodium channel gene, SCN1A, that is responsible for two forms of dominant epilepsy; Generalized Epilepsy with Febrile Seizures Plus (GEFS+) and Severe Myoclonic Epilepsy of Infancy (SMEI or Dravet syndrome). GEFS+ is characterized by febrile (fever induced) seizures that persist beyond the age of six and the development of adult epilepsy. Dravet syndrome is a severe, debilitating childhood epilepsy characterized by febrile and afebrile seizures, mental retardation and ataxia.

 

Understanding the mechanism of epilepsy

Understanding the mechanisms that lead to disease is an important step towards the development of improved therapies. In order to understand how specific mutations cause epilepsy, we have generated mice that carry mutations that were identified in patients with epilepsy. These mice reproduce many features of the human disease including spontaneous seizures, increased seizure susceptibility, and response to human anti-epilepsy medications. A number of mouse models of epilepsy are currently under investigation in our lab.

 

Development of novel treatments for epilepsy

A large number (approximately 40%) of patients with epilepsy do not achieve effective seizure control with available anti-epilepsy medications. We are actively using our mouse models of epilepsy to evaluate the efficacy of alternative treatments such as the ketogenic diet. We are also working to develop novel treatments.

 

 

Two research projects that we have recently initiated are briefly described below.

 

Project 1. Towards a new treatment for Dravet Syndrome

The voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are key regulators of neuronal excitability in the brain. Mutations in SCN1A, SCN2A, and SCN3A are associated with several epilepsy subtypes, including generalized epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In striking contrast, we have observed increased seizure resistance in mice with mutations in Scn8a (this is the equivalent of the human SCN8A gene. By scientific convention, human genes are written in uppercase and mouse genes in lowercase). Furthermore, we were able to restore normal seizure thresholds and lifespans in mouse models of GEFS+ and SMEI by genetically altering the activity of Scn8a. Based on these observations, we hypothesize that abnormal neuronal excitability can be modulated by selectively reducing the expression level of SCN8A, thereby providing a potentially new approach to the treatment of epilepsy. Since current anti-epilepsy drugs (AEDs) cannot selectively target SCN8A, we will evaluate the possibility of altering neuronal excitability by selectively reducing the expression level of Scn8a in mice. If successful, this proof-of-principle proposal may open up an important new direction for the treatment of refractory epilepsy subtypes.

 

 

Project 2. Towards a better understanding of the genetic basis of epilepsy

The idiopathic generalized epilepsies (IGEs) are a group of epilepsy subtypes characterized by recurring seizures in the absence of detectable brain lesions or metabolic abnormalities. There is a significant genetic contribution to the etiology of IGE, with ~18 genes associated with IGE to date. Most of these genes, for example SCN1A, are known to be responsible for rare forms of dominant epilepsy. This observation has led to the hypothesis that relatively infrequent mutations in a large number of genes that influence neuronal excitability may account for a significant portion of common forms of IGE. This hypothesis can be tested directly by screening a large number of candidate genes for disease-causing mutations in epilepsy patients. However, traditional sequence analysis is time-consuming and costly, making this type of experiment prohibitively expensive. Fortunately, recent advances now make it feasible to identify genetic variants in large numbers of candidate genes, and at a reasonable cost. We recently received funding from the Epilepsy Foundation to initiate a pilot study to develop a cost effective, high throughput approach to enable the simultaneous screening of a large number of candidate genes in patients with epilepsy. This study has the potential to not only identify new epilepsy causing genes/mutations, but also to identify genetic variants that may ameliorate seizure severity.

 

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