title: Translational approach for gene therapy in epilepsy: Model system and unilateral overexpression of neuropeptide Y and Y2 receptors.
abstract: 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 the present study, a conceptually novel framework reflecting a plausible clinical trial for gene therapy of temporal lobe epilepsy was explored: We investigated (i) whether the post intrahippocampal kainate-induced status epilepticus (SE) model of chronic epilepsy in rats could be clinically relevant; and (ii) whether a translationally designed neuropeptide Y (NPY)/Y2 receptor-based gene therapy approach targeting only the seizure-generating focus unilaterally can decrease seizure frequency in this chronic model of epilepsy. Our data suggest that the intrahippocampal kainate model resembles the disease development of human chronic mesial temporal lobe epilepsy (mTLE): (i) spontaneous seizures originate in the sclerotic hippocampus; (ii) only a part of the animals develops chronic epilepsy; (iii) animals show largely variable seizure frequency that (iv) 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. 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, but even 45% decrease of seizure frequency in 80% of the epileptic animals. 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 to develop a future treatment strategy for severe, often pharmacoresistant focal epilepsy cases that cannot be offered alternative therapeutic options.
authors.affiliation: Experimental Epilepsy Group, Epilepsy Centre, Lund University Hospital, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Litsa Nikitidou
authors.initials: LN
authors.lastname: Ledri
authors.affiliation: Experimental Epilepsy Group, Epilepsy Centre, Lund University Hospital, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Esbjörn
authors.initials: E
authors.lastname: Melin
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, Nørregade 10, 1017 Copenhagen, Denmark.
authors.forename: Søren H
authors.initials: SH
authors.lastname: Christiansen
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, Nørregade 10, 1017 Copenhagen, Denmark.
authors.forename: Casper R
authors.initials: CR
authors.lastname: Gøtzsche
authors.affiliation: Experimental Epilepsy Group, Epilepsy Centre, Lund University Hospital, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cifra
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, Nørregade 10, 1017 Copenhagen, Denmark.
authors.forename: David P D
authors.initials: DP
authors.lastname: Woldbye
authors.affiliation: Experimental Epilepsy Group, Epilepsy Centre, Lund University Hospital, Sölvegatan 17, 221 84 Lund, Sweden. Electronic address: Merab.Kokaia@med.lu.se.
authors.forename: Mérab
authors.initials: M
authors.lastname: Kokaia
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D000229:Dependovirus / Q000235:genetics; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000235:genetics* / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007608:Kainic Acid / Q000008:administration & dosage; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000235:genetics*; D057170:Translational Research, Biomedical
chemical_list: D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D007608:Kainic Acid
keywords: Adeno-associated viral vectors; Gene therapy; Intrahippocampal kainate injection; Neuropeptides; Spontaneous seizures