Investigational WNT-pathway modulators for the treatment and prevention of drug-resistant seizures

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ABSTRACT Numerous promising investigational therapies for the treatment of epilepsy have been identified using well- established animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have all been utilized as primary models of electrically or chemically evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which network hyperexcitability has developed, have been used to identify new and highly impactful agents, such as levetiracetam. This screening approach has successfully identified several marketed drugs to manage the symptomatic seizures associated with epilepsy. Despite the numerous antiseizure drugs (ASDs) on the market today, nearly 30% of patients with epilepsy are resistant to these currently available medications. Further, no treatment has yet been identified to slow or prevent the development of epilepsy altogether. To address this unmet medical need, more effective and better tolerated treatments are still desperately needed by the patient with epilepsy. Our group has recently uncovered the antiseizure efficacy of several repurposed therapeutic agents that engage untapped molecular targets associated with normal nervous system development and tissue homeostasis in adulthood. Further, we have demonstrated in a mouse model of evoked chronic seizures that repeated administration of repurposed agents is well-tolerated and can possibly disrupt the formation of a hyperexcitable neuronal network, suggesting a possible disease modifying effect. This study will therefore extend the antiseizure efficacy profile of these two promising investigational compounds for the treatment of symptomatic seizures to establish a pharmacokinetic and pharmacodynamic relationship, as well as assess their potential to prevent epilepsy altogether in well-established rodent seizure and epilepsy models. We will use a clinically relevant rat model of acquired epilepsy that provides a valid platform on which to evaluate the disease-modifying potential of two promising candidate compounds. This study aims to further characterize the therapeutic potential of two promising compounds for the treatment of acute seizures, as well as define the extent to which treatment modifies the onset of spontaneous recurrent seizures, i.e., demonstrate whether epilepsy is delayed or prevented. Further, this study will determine whether the use of novel repurposed agents with promising preliminary efficacy profiles demonstrate the potential to be first-in-class therapies for the treatment, and possibly prevention, of epilepsy.