Can We Panelize Seizure?

Area of Science:

• Neuroscience
• Drug Discovery
• Toxicology

Background:

• Seizure liability is a major cause of attrition in drug discovery, leading to significant financial losses and development delays.
• Current in vivo methods for detecting drug-induced seizures, relying on observable movements, are prone to missed or misinterpreted results, necessitating electroencephalogram confirmation.
• Early screening for cardiac adverse events has successfully reduced attrition; a similar approach is needed for seizure risk.

Purpose of the Study:

• To evaluate the potential of developing an in vitro assay for early prediction of seizurogenic risk in drug candidates.
• To identify key molecular targets, including ion channels, GPCRs, and transporters, implicated in seizure development.
• To enable early elimination of compounds with pro-seizurogenic potential during the drug design phase.

Main Methods:

• Utilizing microelectrode arrays to detect seizurogenic signals from stem cell-derived neurons.
• Developing an in vitro assessment linked to a panel of ion channel assays.
• Investigating the role of neuronal ion channels, GPCRs, transporters, and glial cell interactions in seizure prediction.

Main Results:

• Demonstrated the feasibility of using microelectrode arrays to detect seizure-related neuronal activity in vitro.
• Identified specific ion channel activities and molecular pathways associated with pro-seizurogenic effects.
• Established a foundation for an in vitro assay to predict seizure liability early in drug discovery.

Conclusions:

• An in vitro seizure prediction assay using stem cell-derived neurons and ion channel profiling can significantly reduce drug discovery attrition.
• This approach allows for early intervention in the structure-activity relationship, guiding medicinal chemists to design safer drug candidates.
• Implementing such assays can mitigate the costly impact of seizure liability, improving the efficiency and competitiveness of drug development.