Combinatorial gene therapy for epilepsy: Gene sequence positioning and AAV serotype influence expression and inhibitory effect on seizures
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Combinatorial gene therapy for epilepsy : Gene sequence positioning and AAV serotype influence expression and inhibitory effect on seizures. / Melin, Esbjörn; Andersson, My; Gøtzsche, Casper R.; Wickham, Jenny; Huang, Yuzhe; Szczygiel, Julia Alicja; Boender, Arnie; Christiansen, Søren H.; Pinborg, Lars; Woldbye, David P.D.; Kokaia, Merab.
In: Gene Therapy, Vol. 30, 2023, p. 649-658.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Combinatorial gene therapy for epilepsy
T2 - Gene sequence positioning and AAV serotype influence expression and inhibitory effect on seizures
AU - Melin, Esbjörn
AU - Andersson, My
AU - Gøtzsche, Casper R.
AU - Wickham, Jenny
AU - Huang, Yuzhe
AU - Szczygiel, Julia Alicja
AU - Boender, Arnie
AU - Christiansen, Søren H.
AU - Pinborg, Lars
AU - Woldbye, David P.D.
AU - Kokaia, Merab
N1 - Publisher Copyright: © 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - Gene therapy with AAV vectors carrying genes for neuropeptide Y and its receptor Y2 has been shown to inhibit seizures in multiple animal models of epilepsy. It is however unknown how the AAV serotype or the sequence order of these two transgenes in the expression cassette affects the actual parenchymal gene expression levels and the seizure-suppressant efficacy. To address these questions, we compared three viral vector serotypes (AAV1, AAV2 and AAV8) and two transgene sequence orders (NPY-IRES-Y2 and Y2-IRES-NPY) in a rat model of acutely induced seizures. Wistar male rats were injected bilaterally with viral vectors and 3 weeks later acute seizures were induced by a subcutaneous injection of kainate. The latency until 1st motor seizure, time spent in motor seizure and latency to status epilepticus were measured to evaluate the seizure-suppressing efficacy of these vectors compared to an empty cassette control vector. Based on the results, the effect of the AAV1-NPY-IRES-Y2 vector was further investigated by in vitro electrophysiology, and its ability to achieve transgene overexpression in resected human hippocampal tissue was evaluated. The AAV1-NPY-IRES-Y2 proved to be better to any other serotype or gene sequence considering both transgene expression and ability to suppress induced seizures in rats. The vector also demonstrated transgene-induced decrease of glutamate release from excitatory neuron terminals and significantly increased both NPY and Y2 expression in resected human hippocampal tissue from patients with drug-resistant temporal lobe epilepsy. These results validate the feasibility of NPY/Y2 receptor gene therapy as a therapeutic opportunity in focal epilepsies.
AB - Gene therapy with AAV vectors carrying genes for neuropeptide Y and its receptor Y2 has been shown to inhibit seizures in multiple animal models of epilepsy. It is however unknown how the AAV serotype or the sequence order of these two transgenes in the expression cassette affects the actual parenchymal gene expression levels and the seizure-suppressant efficacy. To address these questions, we compared three viral vector serotypes (AAV1, AAV2 and AAV8) and two transgene sequence orders (NPY-IRES-Y2 and Y2-IRES-NPY) in a rat model of acutely induced seizures. Wistar male rats were injected bilaterally with viral vectors and 3 weeks later acute seizures were induced by a subcutaneous injection of kainate. The latency until 1st motor seizure, time spent in motor seizure and latency to status epilepticus were measured to evaluate the seizure-suppressing efficacy of these vectors compared to an empty cassette control vector. Based on the results, the effect of the AAV1-NPY-IRES-Y2 vector was further investigated by in vitro electrophysiology, and its ability to achieve transgene overexpression in resected human hippocampal tissue was evaluated. The AAV1-NPY-IRES-Y2 proved to be better to any other serotype or gene sequence considering both transgene expression and ability to suppress induced seizures in rats. The vector also demonstrated transgene-induced decrease of glutamate release from excitatory neuron terminals and significantly increased both NPY and Y2 expression in resected human hippocampal tissue from patients with drug-resistant temporal lobe epilepsy. These results validate the feasibility of NPY/Y2 receptor gene therapy as a therapeutic opportunity in focal epilepsies.
U2 - 10.1038/s41434-023-00399-w
DO - 10.1038/s41434-023-00399-w
M3 - Journal article
C2 - 37029201
AN - SCOPUS:85151954375
VL - 30
SP - 649
EP - 658
JO - Gene Therapy
JF - Gene Therapy
SN - 0969-7128
ER -
ID: 344637986