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Searching seizures

While most adverse phenotypes emerging in vivo late in drug development are unpredictable, progress has slowly but surely been made in avoiding drug attrition due to a few common adverse phenotypes. The most well-known of these is hERG channel effect resulting in long QT syndrome in the heart, which can now be rapidly assessed for candidate drugs with an in vitro, albeit somewhat complex, assay. The positive predictive value of hERG has increased attention on “excitable” tissues in general, such as the other (non-conducting) spontaneously contracting heart tissues and electrically active tissues in the brain. The latter are associated with drug-induced seizures, and assessing the seizure “liability” of drug candidates is now a major safety focus in drug development.

Strobe lights

Reliable in vitro assays that recapitulate seizures are critical for rapid assessment of seizure liability during drug development. Researchers from Janssen isolated neurons from the cortex tissues of rat brains and cultured them in vitro as a means of testing their response to drugs known to elicit seizures. The in vitro assay correlated well with more impractical whole, live animal seizure detection via electroencephalogram (EEG). Furthermore, molecular analysis is possible with cultured cells that is not in vivo, and indeed the investigators were able to profile the transcriptomes of the cells exposed to the drugs and use this information to identify off-targets of the drugs that are likely to be responsible for the seizures. This excellent finding may enable the further development of molecular assays for seizure liability, like the hERG channel assay.

The work required isolation of specific brain tissue for testing, demonstrating the importance of tissue specific assessment in drug development. This study found used cortical neurons. The cortex in the brain is the area were seizure activity, as measured by waves of electrical activity on EEG, are most widely observed. The drug targets identified by the researchers are not uniformly expression across the many different brain tissues (hippocampus, thalamus, etc). GeneCentrix’s tools assess drug target expression in all the major brain tissues independently, further enabling these analyses.

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