Sophion-Research-Grant-Ahmed-Eltokhi

Personalized Medicine for Epilepsy: Decoding Drug Resistance in DEE Patients

Dr. Ahmed Eltokhi, assistant professor at Mercer University School of Medicine has been awarded a Sophion Research Grant to work on automated patch clamp alongside Sophion’s Dr. David Nagy in our Bedford, MA, lab. Together they will investigate the effects of antiepileptic drugs on mutations in NaV1.2 sodium channel fenestrations, a key factor in drug-resistant developmental epileptic encephalopathy (DEE). The study is rooted in the “Fenestropathy” hypothesis (Gamal El-Din & Lenaeus, Front. Pharmacol., 2022), which suggests that specific missense mutations in NaV1.2 fenestrations can lead to either a gain- or loss-of-function in sodium currents, impacting seizure development and treatment outcomes.

The research will analyze how eight antiepileptic drugs interact with mutated NaV1.2 channels, exploring drug binding and movement within the channel’s central cavity. By improving the understanding of how structural changes affect drug efficacy, the study aims to pave the way for personalized medicine approaches to treat DEE, a condition affecting cognitive and neurological functions in patients with severe, medication-resistant seizures.

This work promises critical insights into the biophysical underpinnings of DEE, addressing a pressing need for more effective and targeted therapies.

To get more insights into Dr. Eltokhi’s background, the drivers and ambitions for his work, we interviewed him ahead of his Research Grant:

Can you summarize what you’ll work on in Sophion’s labs in a sentence or two?

I’ll use high-throughput automated patch clamp technology to study approximately 15 NaV1.2 channel variants associated with developmental and epileptic encephalopathies. My goal is to identify their shared biophysical properties and examine how these variants impact antiepileptic drug binding and state-dependent drug ingress and egress, potentially contributing to pharmacoresistance in this disorder.

What first inspired you to pursue research in this area of ion channels?

During my PhD at Heidelberg University in collaboration with the Max Planck Institute, I studied how synaptic proteins like SHANK2, NMDA, and AMPA receptors relate to neuropsychiatric disorders such as autism. Although neuropsychiatric disorders are often attributed to developmental synaptopathy, this view doesn’t fully explain their heterogeneity. After my PhD, I wanted to explore these disorders from a different angle. This led me to shift my focus to the axonal level, where I began exploring the role of voltage-gated ion channels in their pathophysiology. Training under Holger Lerche at Hertie Institute for Clinical Brain Research, University of TĂĽbingen and Bill Catterall at the University of Washington deepened my understanding of the field and fueled my passion for understanding autism and DEE, with the ultimate goal of discovering effective therapeutics. My recent work identified a novel mechanism in autism involving gating pore currents in ion channels (Eltokhi et al., PNAS, 2024), which provides new insights into the complexity of autism. Building on Dr. Gamal El-Din’s “Fenestropathy” hypothesis, the current project aligns perfectly with my aspiration to connect fundamental biophysical discoveries to clinical applications. Through this research, I aim to contribute to the advancement of personalized medicine, improving treatment outcomes for patients facing challenging and life-altering conditions.

Have you encountered any unexpected findings or amusing moments in your research?

Reflecting on my early days in the field, I find it both amusing and frustrating that I spent so much time characterizing variants using traditional patch clamp techniques. Learning that automated patch clamp technology could efficiently handle high-throughput data and facilitate the testing of multiple drugs was eye-opening. This realization motivated me to apply for the Sophion Research Grant.

What key challenges have you overcome, or techniques mastered, in your work?

Early in my work on gating pore currents, Drs. Bill Catterall and Gamal El-Din highlighted the difficulty of recording these currents in HEK293 cells, as they account for only 0.1–1% of the central pore current. Achieving high expression levels and current density was critical. Over a year, I developed a method using BACMAM viral transduction and cell cycle arrest to achieve 30–40 nA of central pore current (Eltokhi et al., Cell Reports Methods, 2023). Despite the technical challenges, this breakthrough allowed us to measure tiny gating pore currents, advancing our research significantly.

Where do you see your lab’s work heading in the coming years?

I plan to deepen our understanding of neuropsychiatric and neurological disorders by identifying common pathophysiological mechanisms in voltage-gated ion channels and their variants’ role in drug resistance. I aim to refine mouse models with these mutations to explore potential therapeutic strategies and improve clinical outcomes. My broader goal is to integrate advanced technologies and make meaningful contributions to this field.

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