Commentary: A Skeptical View of Experimental Gene Therapy to Block Epileptogenesis

Abstract

Summary: Gene therapy offers exciting new options for treating epileptic seizures, and even for blocking the development of epilepsy (i.e., epileptogenesis) after a brain insult. Although the available studies provide interesting new data, the experiments discussed in this issue also have limitations and raise concerns. The criticisms offered in this commentary center around the nature of the experimental testing (e.g., changes in seizure threshold), the animal models (e.g., kindling), and the measures of epileptogenesis in those animal models with spontaneous seizures (e.g., the latent period after pilocarpine-induced status epilepticus). Another set of criticisms relate to the relative lack of positive controls showing that the actual mechanism purported to be activated via the gene-therapeutic approach has in fact been upregulated in the specific animals that show the hypothetical antiepileptic result. This commentary takes the con side in the debate, to generate constructive criticism to help direct future studies to provide increasingly stronger data to support the view that gene therapy approaches may be useful in the treatment of epilepsy.

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

“…1 bears similarities to the multistep process of carcinogenesis with initiation, repair or promotion, and progression (Löscher and Liburdy, 1998;Löscher, 2002c). It should be noted, however, that the concept of the latent period and epileptogenesis has been criticized (Sloviter, 2008;Dudek, 2009), which will be discussed in section III.C.3.c.…”

“…Thus, kindling via depth electrodes may represent a model in which the consequences of TBI are facilitated by electrical stimulation. Fourth, for antiepileptogenic drug testing during the kindling acquisition phase, drugs are usually given before each electrical stimulus, so that the acute anticonvulsant effect of each drug administration alone could be sufficient to retard kindling, thus producing false positive data on the antiepileptogenic potential of a given drug (Dudek, 2009).…”

“…The severity and extent of the damage and variability seen after convulsive SE makes it difficult to show that any treatment has a statistically significant antiepileptogenic or disease-modifying protective effect (Sloviter et al, 2007). Furthermore, after a prolonged severe convulsive SE, rats often exhibit only a very short latent period (or no latent period at all) before onset of spontaneous seizures (Bumanglag and Sloviter, 2008;Sloviter, 2008;Dudek, 2009), which would explain why almost all attempts to prevent epileptogenesis after convulsive SE have failed (see section III.C.3.g). As discussed in section III.C.3.g, this problem can be reduced by restricting the duration of the convulsive SE by AEDs or general anesthetics, and by using ramp-up dosing protocols for chemoconvulsants, which allow for a more individual dosing than bolus injections, but animals still show high interindividual variability in the duration of the latent period and the extent of brain damage.…”

“…Soltesz and colleagues reported that rimonabant prevents the development of increased seizure susceptibility when administered during or shortly after a brain insult in models of prolonged febrile seizures (Chen et al, 2007) or TBI (Echegoyen et al, 2009), but such treatment was not effective in modifying the development of spontaneous recurrent seizures in the kainate SE model (Pouliot et al, 2009). This indicates either that the same drug exhibits varying effects in different models of epileptogenic brain insults or, as argued by Dudek (2009), that determining seizure threshold as a measure of increased neuronal hyperexcitability and hence epileptogenesis (as done in the studies by Soltesz and colleagues) is highly susceptible to errors and is indirect, at best.…”

“…The concept of an extended "therapeutic window" or latent period after brain injury has been questioned (Sloviter, 2008;Dudek, 2009). The duration of the latent period (i.e., the time from brain insult to the first spontaneous electrographic or motor seizure) has traditionally been considered to be a measure of epileptogenesis, which formed the conceptual basis for the design and interpretation of antiepileptogenesis studies in post-SE models of TLE (Sloviter, 2008;Dudek, 2009).…”