Disease Modification by Combinatorial Single Vector Gene Therapy: A Preclinical Translational Study in Epilepsy
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Disease Modification by Combinatorial Single Vector Gene Therapy : A Preclinical Translational Study in Epilepsy. / Melin, Esbjörn; Nanobashvili, Avtandil; Avdic, Una; Gøtzsche, Casper R.; Andersson, My; Woldbye, David P.D.; Kokaia, Merab.
In: Molecular Therapy - Methods and Clinical Development, Vol. 15, 2019, p. 179-193.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Disease Modification by Combinatorial Single Vector Gene Therapy
T2 - A Preclinical Translational Study in Epilepsy
AU - Melin, Esbjörn
AU - Nanobashvili, Avtandil
AU - Avdic, Una
AU - Gøtzsche, Casper R.
AU - Andersson, My
AU - Woldbye, David P.D.
AU - Kokaia, Merab
N1 - Publisher Copyright: © 2019 The Authors
PY - 2019
Y1 - 2019
N2 - Gene therapy has been suggested as a plausible novel approach to achieve seizure control in patients with focal epilepsy that do not adequately respond to pharmacological treatment. We investigated the seizure-suppressant potential of combinatorial neuropeptide Y and Y2 receptor single vector gene therapy based on adeno-associated virus serotype 1 (AAV1) in rats. First, a dose-response study in the systemic kainate-induced acute seizure model was performed, whereby the 1012 genomic particles (gp)/mL titer of the vector was selected as an optimal concentration. Second, an efficacy study was performed in the intrahippocampal kainate chronic model of spontaneous recurrent seizures (SRSs), designed to reflect a likely clinical scenario, with magnetic resonance image (MRI)-guided focal unilateral administration of the vector in the hippocampus during the chronic stage of the disease. The efficacy study demonstrated a favorable outcome of the gene therapy, with a 31% responder rate (more than 50% reduction in SRS frequency) and 13% seizure-freedom rate, whereas no such effects were observed in the control animals. The inter-SRS and SRS cluster intervals were also significantly prolonged in the treated group compared to controls. In addition, the SRS duration was significantly reduced in the treated group but not in the controls. This study establishes the SRS-suppressant ability of the single vector combinatorial neuropeptide Y/Y2 receptor gene therapy in a clinically relevant chronic model of epilepsy.
AB - Gene therapy has been suggested as a plausible novel approach to achieve seizure control in patients with focal epilepsy that do not adequately respond to pharmacological treatment. We investigated the seizure-suppressant potential of combinatorial neuropeptide Y and Y2 receptor single vector gene therapy based on adeno-associated virus serotype 1 (AAV1) in rats. First, a dose-response study in the systemic kainate-induced acute seizure model was performed, whereby the 1012 genomic particles (gp)/mL titer of the vector was selected as an optimal concentration. Second, an efficacy study was performed in the intrahippocampal kainate chronic model of spontaneous recurrent seizures (SRSs), designed to reflect a likely clinical scenario, with magnetic resonance image (MRI)-guided focal unilateral administration of the vector in the hippocampus during the chronic stage of the disease. The efficacy study demonstrated a favorable outcome of the gene therapy, with a 31% responder rate (more than 50% reduction in SRS frequency) and 13% seizure-freedom rate, whereas no such effects were observed in the control animals. The inter-SRS and SRS cluster intervals were also significantly prolonged in the treated group compared to controls. In addition, the SRS duration was significantly reduced in the treated group but not in the controls. This study establishes the SRS-suppressant ability of the single vector combinatorial neuropeptide Y/Y2 receptor gene therapy in a clinically relevant chronic model of epilepsy.
U2 - 10.1016/j.omtm.2019.09.004
DO - 10.1016/j.omtm.2019.09.004
M3 - Journal article
AN - SCOPUS:85073575307
VL - 15
SP - 179
EP - 193
JO - Molecular Therapy - Methods and Clinical Development
JF - Molecular Therapy - Methods and Clinical Development
SN - 2329-0501
ER -
ID: 286927249