Seizure Suppression by GDNF Gene Therapy in Animal Models of Epilepsy.

Kanter-Schlifke, Irene; Georgievska, Biljana; Kirik, Deniz; Kokaia, Merab

Temporal lobe epilepsy patients remain refractory to available anti-epileptic drugs in 30% of cases, indicating a need for novel therapeutic strategies. In this context, glial cell line–derived neurotrophic factor (GDNF) emerges as a possible new agent for epilepsy treatment. However, a limited number of studies, use of different epilepsy models, and different methods of GDNF delivery preclude understanding of the mechanisms for the seizure-suppressant action of GDNF. Here we show that recombinant adeno-associated viral (rAAV) vector–based GDNF overexpression in the rat hippocampus suppresses seizures in two models of temporal lobe epilepsy. First, when rAAV-GDNF was injected before hippocampal kindling, the number of generalized seizures decreased, and the prolongation of behavioral convulsions in fully kindled animals was prevented. Second, injection of rAAV-GDNF after kindling increased the seizure induction threshold. Third, rAAV-GDNF decreased the frequency of generalized seizures during the self-sustained phase of status epilepticus. Our data demonstrate the complexity of mechanisms and the beneficial action of GDNF in epilepsy. Furthermore, we show that ectopic rAAV-mediated GDNF gene expression in the seizure focus is a feasible way to mitigate seizures and provides proof of principle that the neurotrophic factor–based gene therapy approach has the potential to be developed as alternative strategy for epilepsy treatment.Molecular Therapy (2007) 15 6, 1106–1113. doi:10.1038/sj.mt.6300148

MEDICAL research; TEMPORAL lobe epilepsy; GENE therapy; THERAPEUTICS; NEUROGLIA; ADENOVIRUSES; NEUROLOGICAL disorders; GENE expression

Molecular Therapy, 2007, Vol 15, Issue 6, p1106

1525-0016

Academic Journal

10.1038/sj.mt.6300148