Article

Seizure Suppression by GDNF Gene Therapy in Animal Models of Epilepsy

Experimental Epilepsy Group, Wallenberg Neuroscience Center, Lund University Hospital, Lund, Sweden.
Molecular Therapy (Impact Factor: 6.23). 07/2007; 15(6):1106-13. DOI: 10.1038/sj.mt.6300148
Source: PubMed

ABSTRACT

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.

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Available from: Merab Kokaia, Mar 24, 2014
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    • "Targeting the hippocampus with gene therapy has recently emerged as a promising alternative treatment strategy for epilepsy. For example, overexpression of endogenous neuropeptides by rAAV vectors in the hippocampus has shown long-lasting inhibition of epileptic seizures in various animal models of epilepsy (Richichi et al., 2004; McCown, 2006; Kanter-Schlifke et al., 2007; Noe et al., 2008). Supporting the validity of the gene therapy approach for neurological diseases, clinical trials in Parkinson's disease have demonstrated its safety, as well as positive therapeutic outcomes (Kaplitt et al., 2007; Marks et al., 2008). "

    Full-text · Dataset · Dec 2015
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    • "Targeting the hippocampus with gene therapy has recently emerged as a promising alternative treatment strategy for epilepsy. For example, overexpression of endogenous neuropeptides by rAAV vectors in the hippocampus has shown long-lasting inhibition of epileptic seizures in various animal models of epilepsy (Richichi et al., 2004; McCown, 2006; Kanter-Schlifke et al., 2007; Noe et al., 2008). Supporting the validity of the gene therapy approach for neurological diseases, clinical trials in Parkinson's disease have demonstrated its safety, as well as positive therapeutic outcomes (Kaplitt et al., 2007; Marks et al., 2008). "

    Full-text · Dataset · Dec 2015
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    • "Targeting the hippocampus with gene therapy has recently emerged as a promising alternative treatment strategy for epilepsy. For example, overexpression of endogenous neuropeptides by rAAV vectors in the hippocampus has shown long-lasting inhibition of epileptic seizures in various animal models of epilepsy (Richichi et al., 2004; McCown, 2006; Kanter-Schlifke et al., 2007; Noe et al., 2008). Supporting the validity of the gene therapy approach for neurological diseases, clinical trials in Parkinson's disease have demonstrated its safety, as well as positive therapeutic outcomes (Kaplitt et al., 2007; Marks et al., 2008). "
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    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 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.
    Full-text · Article · Nov 2015 · Neurobiology of Disease
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