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.

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

The blood-brain barrier (BBB) acts as a double-edged sword in neurological diseases by prohibiting circulating toxins from entering the brain but as a consequence also prohibits the delivery of 98% of small molecule therapeutics into the brain. Our work aims to understand the changes that occur in the BBB during epilepsy to provide evidence of why 30% of patients do not experience seizure freedom after therapeutic intervention. Completion of this work will offer novel approaches for improving drug delivery of commonly prescribed antiseizure medications into the brain. 

This proposal aims to i) understand the molecular alterations of tight junction proteins during epilepsy and the physical size of gaps that occur as a result, and ii) measure altered expression and function of efflux transport proteins P-glycoprotein (P-gp) and breast cancer resistant protein (Bcrp) as a result of either seizure occurrence, administration of ASMs, or both. 

Aim 1: Define alterations in tight junction protein expression and localization before and after seizure onset in vivo.

Aim 2: Define alterations in efflux transport protein expression and function before and after seizure onset in vivo.

To address this, we 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.

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 (EIEE) 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 EIEE. Mutations in a large set of genes have been implicated in the etiology of EIEE, 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 300 patients known worldwide with SCN8A-related epilepsy with encephalopathy, and thousands more with related sodium ion channelopathies.

In our lab, we employ a knock-in mouse carrying the N1768D (D/+) mutation 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.

Human TLE

In collaboration with Dr. Martin Weinand, we have studied alterations in gene expression in brain samples from patients with temporal lobe epilepsy (TLE). We performed RNA-seq on hippocampal tissue resected from 12 medically intractable TLE patients with pre-surgery seizure frequencies ranging from 0.33 to 120 seizures per month. We then performed differential expression (DE) analysis comparing a group patients with an average of 4 seizures per month (LSF) with a second group with an average of 60 seizures per month (HSF). A total of 979 genes with ≥2-fold change in transcript abundance distinguished these groups. When compared with post-mortem hippocampal controls, a total of 1,676 genes were found to be significantly downregulated in HSF patients compared with only 399 downregulated genes in LSF patients.

Pathway analysis revealed >50 significantly deactivated or activated signaling pathways, with Signal Transduction as the central hub in the pathway network. While neuroinflammation pathways were activated in both seizure frequency groups, the HSF group systematically deactivated several key signaling pathways, including calcium, CREB and Opioid signaling.

We also infer that increased expression of the immediate early gene, NPAS4, and a signaling cascade promoting synaptic scaling via AMPA receptors, may have played a key role in maintaining a higher seizure threshold in the LSF cohort. These results suggest that therapeutic approaches targeting synaptic scaling pathways may aid in the treatment of seizures in TLE

Scroll to Top