An in vivo chemical screen for seizure suppression in Duplication 15q syndrome.

University Of Tennessee Health Sci Ctr, Memphis TN

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Abstract

The objective of this study is to perform a chemical screen to identify currently approved medications that can be repurposed as potential anti-epileptics in both Duplication 15q syndrome (Dup15q) and inherited epilepsy. Children with Dup15q have an extremely high incidence of seizures that often begins in the post-natal stage as infantile spasms and later in childhood progresses to epilepsy that is difficult to manage using currently available antiepileptic medications. In this proposal we use a newly developed Drosophila model of Dup15q syndrome that recapitulates the seizure phenotypes observed in humans. We will perform high-throughput screening in fly larval brains to identify compounds that can re-activate gene expression for a specific set of synapse associated genes down regulated in the Dup15q model, some of which are also associated with inherited human epilepsies. We will then attempt to suppress the seizure phenotype in our model using these compounds from our screen and also investigate the molecular consequences of this chemical suppression of seizures. These studies have broad therapeutic implications not only for pediatric disorders like Dup15q syndrome, but also for other inherited forms of epilepsy which result from de novo mutations in synaptic genes. Since the compound libraries we are using contain previously approved drugs, it will be possible to quickly translate our findings to clinical practice in off-label therapeutic intervention studies for epilepsy.