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Disease Modification by Combinatorial Single Vector Gene Therapy : A Preclinical Translational Study in Epilepsy

Melin, Esbjörn LU orcid ; Nanobashvili, Avtandil LU ; Avdic, Una LU ; Gøtzsche, Casper R. ; Andersson, My LU orcid ; Woldbye, David P.D. and Kokaia, Merab LU (2019) In Molecular Therapy - Methods and Clinical Development 15. p.179-193
Abstract

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... (More)

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.

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author
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organization
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type
Contribution to journal
publication status
published
subject
in
Molecular Therapy - Methods and Clinical Development
volume
15
pages
15 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85073575307
  • pmid:31660420
ISSN
2329-0501
DOI
10.1016/j.omtm.2019.09.004
language
English
LU publication?
yes
id
e24142b7-b8a3-471f-9a80-d8a05a072085
date added to LUP
2019-10-25 11:08:20
date last changed
2024-04-16 22:29:32
@article{e24142b7-b8a3-471f-9a80-d8a05a072085,
  abstract     = {{<p>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 10<sup>12</sup> 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.</p>}},
  author       = {{Melin, Esbjörn and Nanobashvili, Avtandil and Avdic, Una and Gøtzsche, Casper R. and Andersson, My and Woldbye, David P.D. and Kokaia, Merab}},
  issn         = {{2329-0501}},
  language     = {{eng}},
  month        = {{12}},
  pages        = {{179--193}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Molecular Therapy - Methods and Clinical Development}},
  title        = {{Disease Modification by Combinatorial Single Vector Gene Therapy : A Preclinical Translational Study in Epilepsy}},
  url          = {{http://dx.doi.org/10.1016/j.omtm.2019.09.004}},
  doi          = {{10.1016/j.omtm.2019.09.004}},
  volume       = {{15}},
  year         = {{2019}},
}