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Gene therapy in temporal lobe epilepsy

ZFI 009770

Summary

Medicine is presently facing a high incidence of drug-resistant focal epilepsies. A subgroup of affected patients can become seizure-free after surgical removal of the epileptogenic focus. However, there remains a large cohort of patients, who cannot be treated sufficiently at present. We and others have recently demonstrated the importance of specific neuropeptides in seizure control in a pharmaco-resistant animal model of temporal lobe epilepsy (TLE). We now want to evaluate the potential of prolonged neuropeptide expression by focal application of transgene-expressing adeno-associated virus (AAV) vectors in an animal model of TLE. We will explore whether prolonged neuropeptide stimulation in selected regions of the hippocampal formation (representing the central structure in TLE) will suppress seizure activity and prevent progression of epilepsy.

It is anticipated that neuropeptide over-expression driven by AAV vectors will result in reduced seizure activity, reduction of neuronal loss and conservation of brain functions. We propose to analyze the effects by means of in-vivo EEG recordings, measuring the frequency and duration of seizure related events like sharp waves, bursts and paroxysmal discharges after injection of kainic acid into the dorsal hippocampus of mice. Histochemical analyses of morphological and pathological changes in brain areas mostly affected in this model will be accompanied by behavioral tests to investigate such brain functions known to be impaired in patients suffering from temporal lobe epilepsy and reproduced in animals models of this disease. These tests will mostly focus on spatial learning abilities and emotional control. One central aspect will be the stability of beneficial effects over a long period of time, as epilepsy cannot be cured presently and patients need life-long treatment.

The long-term goal of our studies is to develop the preclinical model into a gene therapy for patients suffering from refractory mesial temporal lobe epilepsy as well as other types of focal epilepsies.