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

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.

Grant Number: 4R33NS126626-03
NIH Institute/Center: NIH
Principal Investigator: Melissa Barker-Haliski