The challenge and promise of anti-epileptic therapy development in animal models

Abstract

Translation of successful target and compound validation studies into clinically effective therapies is a major challenge, with potential for costly clinical trial failures. This situation holds true for the epilepsies-complex diseases with different causes and symptoms. Although the availability of predictive animal models has led to the development of effective antiseizure therapies that are routinely used in clinical practice, showing that translation can be successful, several important unmet therapeutic needs still exist. Available treatments do not fully control seizures in a third of patients with epilepsy, and produce substantial side-effects. No treatment can prevent the development of epilepsy in at-risk patients or cure patients with epilepsy. And no specific treatment for epilepsy-associated comorbidities exists. To meet these demands, a redesign of translational approaches is urgently needed.

Figure 1. Antiseizure drug screening

Classic Anticonvulsant Screening Program (ASP) testing protocol (A). Proposed testing protocol of the ASP, based on recommendations of the working group that reviewed the programme in 2011 (B). The inclusion of the corneal kindled mouse at the front end provides a chronic seizure model that was missing from the original screening mechanism. LTG=lamotrigine. MES=maximal electroshock. PTZ=pentylenetetrazol. ED50=median effective dose. TD50=median toxic dose. SE=status epilepticus.

Figure 2. Epilepsy biomarkers

The bars at the bottom of each panel indicate epileptogenic mechanisms (M1, M2, and M3) involved in the development of an epilepsy condition. Some of these processes are time-limited and others can continue as the enduring epileptogenic abnormality responsible for the propensity to generate spontaneous seizures, in response to precipitating factors that might or might not be easily identified. The red line represents the seizure threshold, which decreases during epileptogenesis to a point at which spontaneous seizures can occur. Epileptogenesis (A). The cascade of epileptogenic mechanisms can be measured at points 1 and 2. These points and might enable staging of the epileptogenic process. The existence of an enduring epileptogenic abnormality can be measured at points 3 and 4, and other measures at these timepoints could indicate that the seizure threshold is at a level where spontaneous seizures can occur. Progression (B). The cascade of epileptogenic abnormalities at points 1 and 2 would be similar to that in part A, but measures at points 3 and 4 would show that a more pronounced epileptogenic abnormality persists. These timepoints would also indicate that the threshold continues to decrease, causing seizures to be more frequent and more severe. Remission (C). Following an intervention after point 3, a measurement at point 4 would show that the threshold is raised above the level at which spontaneous seizures occur; however, the epileptogenic abnormality persists. This persistence is in contradistinction to cure (D). In this case, a measurement taken at point 4 would show that the return of threshold to a normal level is due to the fact that the epileptogenic abnormality has gone. Prevention (E), in which an intervention between points 1 and 2 results in a complete elimination of the epileptogenic process. Measurements at points 3 and 4 would then show that the threshold never dips below a level at which spontaneous seizures would occur, and that an epileptogenic abnormality never developed. Reproduced from Engel and colleagues, by permission of John Wiley and Sons.

Figure 3. Different phases of preclinical therapy discovery with the proposal of optional preclinical trials

One option that could be considered to enable translation and de-risk clinical studies is the organisation of multicentre preclinical studies modelled on phase 2 or 3 clinical trials.