Importance of Research

Basic laboratory research is critical to discovering the ways a normal brain becomes an epileptic brain and to finding better ways to stop seizures. While it is known that epilepsy is an imbalance between excitatory and inhibitory processes, we currently do not understand how a genetic abnormality or an injury to the brain gives rise to epilepsy.

Research has shown that the processes leading to seizures, known as epileptogenesis, involve changes in gene expression, the "rewiring" of brain connections, and the death or birth of specific brain cells. Additional research is needed to more fully understand how seizures start, spread and stop, and how antiepileptic drugs (AEDs) work on brain cells to block seizures.

SEHRF Projects: Supporting Cutting Edge Research

Functional Studies

Uncovering the effects of changes in molecules, channels and brain cells in epilepsy and brain disorders 


Functional Studies: Uncovering the effects of changes in molecules, channels and brain cells in epilepsy and brain disorders

A key area of epilepsy research addresses the role of changes in ion channels in epileptogenesis. Ion channels are molecules on the surface of brain cells that control neural activity. These molecules form pores and are permeable to specific ions that play fundamental roles in inter- and intracellular communication and neuronal excitability. Ion channel mutations comprise nearly half of the mutations identified in epilepsy genes. Experimental models based on the expression of ion channel genes in human cell lines are a powerful and cost-efficient approach to screen genetic variants and reveal mechanisms of how mutations alter ion channel function.

Experimental methods capable of assessing extremely small changes in ion channel activity from the level of a single receptor to a complex neuronal network are used to both understand how dysfunctional ion channels contribute to disease and to test therapeutic agents in their ability to correct that dysfunction. Important research has focused on how neurons communicate with each other (known as neuronal plasticity), on how mutations alter the function of voltage- gated ion channels (ion channels that open and close in response to changes in electrical potential across the cell membrane), as well as on how neurotransmitters and their receptors function in the membranes of neurons. All of these studies are relevant for understanding the mechanism of antiepileptic drug action, and why these drugs do not always work for everyone.

In addition to changes in neurotransmitters and ion channels, it is becoming evident that the process of epileptogenesis is associated with changes in mitochondrial function, energy supply, the production of harmful oxygen species, and inflammation in the brain. Immune cells profoundly influence normal brain function and clearly play a role in the pathogenesis of rare epileptic syndromes and other neurological disorders.


Understanding and testing treatments that we can apply to humans


Understanding and testing treatments that we can apply to humans

Given the difficulty of accessing human epileptic tissue, animal models of epilepsy are crucial for understanding the process of epileptogenesis. Animal seizure models are also required for the identification of potential therapeutic agents for the treatment of epilepsy. However, many of the currently available antiepileptic drugs come from discovery programs that were based on the ability of an investigational drug to reduce seizures that are ‘artificially’ induced either by chemical agent or electrical stimulus.

SEHRF believes that new strategies are needed that make use of animal models of epilepsy that are based on genetic mutations that are known to cause seizures in the human patient. For example, genes coding for various ion channels have been found to cause epilepsy in children and have been introduced into certain strains of mice using gene-editing techniques, like CRISPR/Cas9. Once engineered in the mouse, these ion channel mutations cause seizures that resemble those in the human.

The same mutation identified in Shay’s SCN8A gene has been genetically engineered in two mouse strains, each showing slightly different seizure types that are found in children with SCN8A-related epilepsy syndrome. Studies of these mouse models are beginning to reveal mechanisms and promising results with novel therapeutic agents.

The latest developments provide the possibility for interfering with the expression of specific genes at defined time points during epileptogenesis or at the chronic epileptic stage, to identify and dissect the critical molecular and cellular processes that precede the onset of seizures, and that maintain them once they have started. One avenue for translating these discoveries to the clinic is to identify the genes and pathways that are altered in both the animal model and in humans.

One of SEHRF’s goals is to fund research that makes use of animal models of human epilepsy to identify promising new therapies that improve the quality of life for children with difficult to control seizures.


Discovering the cellular pathways that underlie childhood epilepsy and brain disorders


Omics: Discovering the cellular pathways that underlie childhood epilepsy and brain disorders

‘Omics’ is a term that refers to the next generation of laboratory tools that are revealing more about the specific molecular makeup of an individual. Omic technologies have made it possible to perform many complex tests in a much shorter time than traditional approaches. The rapid accumulation and wide availability of omics data generated by these technologies offer great opportunities to unravel the mechanisms of disease.

Omics research spans DNA, RNA and protein data from the entire assortment of molecules in the cells of an individual. Unlike previous studies on single molecules, omics gains insights into the complex interplay among the molecules that are responsible for progression of complex diseases such as disorders involving the brain. In other words, omics focuses on molecular networks or pathways that underlying the complex interactions in cells.

With the large-scale generation and integration of omic data, pathway and network-based methods provide a more effective means for identifying the abnormal processes underlying epileptic disorders, and for discovering new biomarkers of the disease. Developing technologies that target the specific factors that alter the production of gene products, whether at the level of the gene, the encoded RNA, the protein product or its proper trafficking in the cell, is an important priority to establish new approaches to inhibit epileptogenesis and to stop seizures.

SEHRF supports omics research with the goal of improving our ability to prevent and treat childhood epilepsy and neurological disease.


Translating discoveries from human cells to human lives


Neuronal Cell Lines: Translating discovery in human cells to human lives

A crucial step in translating research on animal models is to develop human models of epilepsy that can be studied in the laboratory. Gene expression patterns and pathway utilization in the brain may differ between mice and humans. Thus, there is a need for neural models that better reflect processes occurring in human brain cells and circuits.

One strategy is to establish cell lines that come from patients to directly study the effect of drugs and compounds on human brain cells. The discovery that an adult cell taken from blood or skin can be reprogrammed to behave like an embryonic stem cell has greatly improved our ability to discover disease mechanisms in the laboratory. These permanent cell lines are known as induced pluripotent stem cells or iPSCs. As the name implies, these cells are pluripotent, which means that they have the pootential to form different adult cell types.

Patients with different mutations in the same gene can have different types and severity of seizures, as well as different clinical responses to drug treatment. The unique advantage of iPSCs is that they allow for the study of human disease in the context of a person’s unique genetic constellation, in disease-relevant cellular subtypes, as well as providing a platform for examining the effects of disease-associated genetic variants in early developmental stages.

The study of iPSC models of epilepsy provides the opportunity to bridge the gap between studies in animal models and clinical trials in humans. We believe that an important first step is to examine the cross-correlation of findings among different models—that is, the functional effects of mutations or the response to pharmacological treatments—by studying the same genetic variants across mouse models, various cellular models, and iPSC-derived patient neurons.

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