Neuropeptide Y gene therapy decreases chronic spontaneous seizures in a rat model of temporal lobe epilepsy

Abstract

Temporal lobe epilepsy remains amongst the most common and drug refractory of neurological disorders. Gene therapy may provide a realistic therapeutic approach alternative to surgery for intractable focal epilepsies. To test this hypothesis, we applied here a gene therapy approach, using a recombinant adeno-associated viral (rAAV) vector expressing the human neuropeptide Y (NPY) gene, to a progressive and spontaneous seizure model of temporal lobe epilepsy induced by electrical stimulation of the temporal pole of the hippocampus, which replicates many features of the human condition. rAAV-NPY or a control vector lacking the expression cassette (rAAV-Empty) was delivered into the epileptic rat hippocampi at an early progressive stage of the disease. Chronic epileptic rats were video-EEG monitored to establish pre-injection baseline recordings of spontaneous seizures and the effect of rAAV-NPY versus rAAV-Empty vector injection. Both non-injected stimulated controls and rAAV-empty injected rats showed a similar progressive increase of spontaneous seizure frequency consistent with epileptogenesis. The delivery of rAAV-NPY in epileptic rat brain leads to a remarkable decrease in the progression of seizures as compared to both control groups and this effect was correlated with the NPY over-expression in the hippocampus. Moreover, spontaneous seizure frequency was significantly reduced in 40% of treated animals as compared to their pre-injection baseline. Our data show that this gene therapy strategy decreases spontaneous seizures and suppresses their progression in chronic epileptic rats, thus representing a promising new therapeutic strategy.

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

“…The data in Figure 2 of Noé et al 10 show that the animals treated with AAV-NPY had an overall lower seizure rate than the two control groups. Nonetheless, as expected, the data in this figure suggest considerable variability within and across animals (compare controls and empty-virus groups), and raises the question: how different were the AAV-NPY animals from the two control groups?…”

“…Nonetheless, as expected, the data in this figure suggest considerable variability within and across animals (compare controls and empty-virus groups), and raises the question: how different were the AAV-NPY animals from the two control groups? The data in Figure 2 and Table 1 of Noé et al 10 suggest that the main effect of the AAV-NPY animals compared to the two control groups was to reduce the variance by decreasing the number of days with relatively high seizure rates, so that the seizure frequency of the empty-AAV control group after injection was one or a few seizures per day, whereas the experimental AAV-NPY group had between one seizure per day to one seizure every few days; therefore, the baseline and post-treatment seizure rate was quite low and variable, and the differences between groups represent relatively few seizures in relation to the amount of recording time, leading to the authors' statement that the "unequivocal demonstration of this hypothesis requires a longer follow-up study of spontaneous seizures." Furthermore, it is unknown whether temporary suppression of seizures, independent of an effect on any other possible antiepileptogenic mechanism, slows the progressive increase in seizure frequency (i.e., do seizures beget seizures?…”

“…In a recent study by Noé et al, 10 an AAV viral vector that increased the expression of neuropeptide Y in the hippocampus (AAV-NPY) reduced the frequency of spontaneous recurrent seizures compared to controls when administered Ͼ3 months after induction of status epilepticus. Seizure frequency was analyzed over periods of 2 weeks before and 4 weeks after administration of the AAV-NPY, and was compared to similar recordings from animals that were sham controls and those that received empty AAV.…”

“…Therefore, if AAV-NPY acutely suppresses seizures, it may secondarily reduce the progressive increase in seizure frequency after status epilepticus. Noé et al 10 also emphasize the need for further studies showing that learning, memory, and other brain functions are not adversely affected by the AAV-NPY. In conclusion, although the data are not without caveats and concerns, these studies provide the most comprehensive and encouraging data to date that a gene therapy approach suppresses spontaneous recurrent seizures and may actually be antiepileptogenic (or at least, disease modifying).…”

Opioidrezeptoragonisten

“…Für die Neuropeptide Galanin und Neuropeptid Y wurden virale Vektoren entwickelt, um eine eventuelle krankheitsmodifizierende Funktion zu untersuchen. Erste Ergebnisse aus tierexperimentellen Untersuchungen demonstrierten sowohl eine antikonvulsive Wirkung als auch eine positive Wirkung in Bezug auf die Krankheitsprogression [19]. Für die Neuropeptide Somatostatin und Neurotensin laufen derzeit klinische Studien [26].…”