Gene therapy against intractable epilepsy: promising proof of concept study

Although novel treatment strategies based on the gene therapy approach for epilepsy has been encouraging, there is still a gap in demonstrating a proof-of-concept in a clinically relevant animal model and study design.

In a study published in Neurobiology of Disease on Dec 1, 2015 researchers from Lund University in Sweden and colleagues at University of Copenhagen Denmark delivered genes for a signal substance "neuropeptide Y" and its receptor into the brain of test animals with post intrahippocampal kainate-induced status epilepticus (SE) model of chronic epilepsy, and succeeded in considerably reducing the number of epileptic seizures among the animals. The test has been designed to as far as possible mimic a future situation involving treatment of human patients.

Neuropeptide Y (NPY), which is widely expressed in the brain, is involved in various brain functions, including regulation of neuronal excitability and seizures.

The intrahippocampal kainate model resembles the disease development of human chronic mesial temporal lobe epilepsy (mTLE) in that spontaneous seizures originate in the sclerotic hippocampus, only a part of the animals develops chronic epilepsy, animals show largely variable seizure frequency and tends to progressively increase over time.

Despite significant hippocampal degeneration caused by the kainate injection, the use of MRI allowed targeting the recombinant adeno-associated viral (rAAV) vectors encoding NPY and Y2 receptor genes to the remaining dorsal and ventral hippocampal areas ipsilateral to the kainate injection.

The study results have so far been positive.Continuous video-EEG monitoring demonstrated not only prevention of the progressive increase in seizure frequency in rAAV-NPY/Y2 treated animals as compared to the controls, and for 80 % of the animals the number of seizures was reduced by almost half.

This translationally designed study in a clinically relevant model of epilepsy suggests that simultaneous overexpression of NPY and Y2 receptors unilaterally in the seizure focus is a relevant and promising approach that can be further validated in more extensive preclinical studies.

Gene therapy treatments could initially be carried out on patients who have already been selected for surgical procedures. In the long term, however, gene therapy will be of the greatest benefit to those patients who cannot be operated on.

There are patients with severe epilepsy whose epileptic focus is so badly placed that an operation is out of question since it can impair e.g. speech or movement. These patients can therefore never undergo a surgical procedure, but could be helped by gene therapy in the future.

Citation: Translational approach for gene therapy in epilepsy: Model system and unilateral overexpression of neuropeptide Y and Y2 receptors, Ledri LN, Melin E, Christiansen SH, Gøtzsche CR, Cifra A, Woldbye DP, Kokaia M, Neurobiology of Disease , doi: 10.1016/j.nbd.2015.11.014, published online 1 December 2015.

Cover image: Translational pre-clinical design of the study. A schematic overview of plausible interventions for epilepsy treatment using viral vector-based gene therapy for epilepsy patients. The pre-clinical study in rats has been designed based on a clinical perspective for possible future clinical trials in patients with intractable temporal lobe epilepsy and that are candidates for surgical resection of the epileptic focus.