HAMMER LAB RESEARCH
Our research focus is to understand the process of epileptogenesis and to identify novel therapies that reduce seizures and that improve the quality of life of children with epilepsy. The lab combines different technologies and approaches including genomics and functional studies. Learn more about our research and areas of study below.
Publications
OUR RESEARCH
Developing Machine Learning Tools
The Hammer Lab leverages patient data from the International SCN8A Patient Registry and electronic medical records to develop machine learning tools to aid in diagnosis, prognosis, and treatment of individuals with SCN8A variants. Using ML techniques, the Hammer Lab has furthered the understanding of the SCN8A phenotypic landscape. Additionally, ML models have been developed to classify variants as gain- or loss-of-function and predict the clinical subgroup and progression based on clinically relevant data found within the Registry.
MOUSE MODELS
One of our goals is to understand the mechanisms that lead to epilepsy and developmental impairments. To address these questions, we have developed a novel mouse model introducing a knock-in gain-of-function mutation (SCN8A n.N1768D) into C57BL/6 mice. The canonical gene encodes for a voltage-gated sodium ion channel (NaV1.6) critical for regulating neuronal activity whereas the mutation promotes neuronal excitability. Completion of this work will offer novel approaches for improving drug delivery of commonly prescribed antiseizure medications into the brain.
Longitudinal Studies
We are conducting studies on the progression of SCN8A-related disorders that capture the development of the disease as an individual ages. By using data collected in the Registry and in electronic medical records, we are able to develop clinical timelines for individuals to improve our understanding of features that are predictive of both seizure and non-seizure outcomes later in life. The aim of these studies is to provide valuable insights into what features are important for symptom management and improving the quality of life in individuals. These studies also inform the construction of machine learning tools to use in clinical settings.
INDUCED PLURIPOTENT STEM CELLS
In collaboration with Dr. Lalitha Madhavan, we have established a human pluripotent stem cell (iPSC) model with the SCN8A-N1768D variant to complement pathophysiological studies in the mouse, and to enhance therapeutic potential.
Epilepsy afflicts approximately 750,000 children in the United States and ~45,000 children suffer severe forms beginning in infancy. Early infantile epileptic encephalopathies are a devastating form of epilepsy characterized by global developmental delays, motor and speech deficits, autism, and intractable seizures with a high risk of sudden death (SUDEP). Unfortunately, conventional and newer anti-epileptic drugs control the seizures of only a small percentage of children with epilepsy. Mutations in a large set of genes have been implicated in the etiology of epilepsy, several of which are in voltage gated ion channels.
In 2012, the Hammer lab discovered the first mutation (SCN8A-N1768D) in the sodium channel SCN8A (Nav1.6) in a patient with early onset intractable seizures, developmental delay, and SUDEP. There are now over 850 patients known worldwide with SCN8A-related disorders (SCN8A-RD) and thousands more with related sodium ion channelopathies.
In our lab, we employ both human clinical data and transgenic mouse models to understand the mechanisms and therapeutics and SCN8A-RD. Our mouse model carries the human derived N1768D (D/+) variant to test therapeutic interventions in an animal model that is more representative of human epilepsy than current chemical-induced animal models. In collaboration with Dr. Lalitha Madhavan, we have established a human pluripotent stem cell (iPSC) line with the N1768D variant to complement pathophysiological studies in the mouse, and to enhance therapeutic potential.