Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy
Abstract Focal epilepsy represents one of the most common chronic CNS diseases. The high incidence of drug resistance, devastating comorbidities, and insufficient responsiveness to surgery pose unmet medical challenges. In the quest of novel, disease‐modifying treatment strategies of neuropeptides r...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-09-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201809963 |
| _version_ | 1827015138555723776 |
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| author | Alexandra S Agostinho Mario Mietzsch Luca Zangrandi Iwona Kmiec Anna Mutti Larissa Kraus Pawel Fidzinski Ulf C Schneider Martin Holtkamp Regine Heilbronn Christoph Schwarzer |
| author_facet | Alexandra S Agostinho Mario Mietzsch Luca Zangrandi Iwona Kmiec Anna Mutti Larissa Kraus Pawel Fidzinski Ulf C Schneider Martin Holtkamp Regine Heilbronn Christoph Schwarzer |
| author_sort | Alexandra S Agostinho |
| collection | DOAJ |
| description | Abstract Focal epilepsy represents one of the most common chronic CNS diseases. The high incidence of drug resistance, devastating comorbidities, and insufficient responsiveness to surgery pose unmet medical challenges. In the quest of novel, disease‐modifying treatment strategies of neuropeptides represent promising candidates. Here, we provide the “proof of concept” that gene therapy by adeno‐associated virus (AAV) vector transduction of preprodynorphin into the epileptogenic focus of well‐accepted mouse and rat models for temporal lobe epilepsy leads to suppression of seizures over months. The debilitating long‐term decline of spatial learning and memory is prevented. In human hippocampal slices obtained from epilepsy surgery, dynorphins suppressed seizure‐like activity, suggestive of a high potential for clinical translation. AAV‐delivered preprodynorphin expression is focally and neuronally restricted and release is dependent on high‐frequency stimulation, as it occurs at the onset of seizures. The novel format of “release on demand” dynorphin delivery is viewed as a key to prevent habituation and to minimize the risk of adverse effects, leading to long‐term suppression of seizures and of their devastating sequel. |
| first_indexed | 2024-03-07T18:43:21Z |
| format | Article |
| id | doaj.art-480489b3db774418b348f8ecb6933d15 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:17:49Z |
| publishDate | 2019-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-480489b3db774418b348f8ecb6933d152024-10-28T08:58:04ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-09-01111011610.15252/emmm.201809963Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsyAlexandra S Agostinho0Mario Mietzsch1Luca Zangrandi2Iwona Kmiec3Anna Mutti4Larissa Kraus5Pawel Fidzinski6Ulf C Schneider7Martin Holtkamp8Regine Heilbronn9Christoph Schwarzer10Department of Pharmacology, Medical University of InnsbruckInstitute of Virology, Campus Benjamin Franklin, Charité ‐ Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of HealthDepartment of Pharmacology, Medical University of InnsbruckDepartment of Pharmacology, Medical University of InnsbruckDepartment of Pharmacology, Medical University of InnsbruckDepartment of Neurology, Charité ‐ Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of Health, Epilepsy‐Center Berlin‐BrandenburgDepartment of Neurology, Charité ‐ Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of Health, Epilepsy‐Center Berlin‐BrandenburgDepartment of Neurosurgery, Charité ‐ Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of HealthDepartment of Neurology, Charité ‐ Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of Health, Epilepsy‐Center Berlin‐BrandenburgInstitute of Virology, Campus Benjamin Franklin, Charité ‐ Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of HealthDepartment of Pharmacology, Medical University of InnsbruckAbstract Focal epilepsy represents one of the most common chronic CNS diseases. The high incidence of drug resistance, devastating comorbidities, and insufficient responsiveness to surgery pose unmet medical challenges. In the quest of novel, disease‐modifying treatment strategies of neuropeptides represent promising candidates. Here, we provide the “proof of concept” that gene therapy by adeno‐associated virus (AAV) vector transduction of preprodynorphin into the epileptogenic focus of well‐accepted mouse and rat models for temporal lobe epilepsy leads to suppression of seizures over months. The debilitating long‐term decline of spatial learning and memory is prevented. In human hippocampal slices obtained from epilepsy surgery, dynorphins suppressed seizure‐like activity, suggestive of a high potential for clinical translation. AAV‐delivered preprodynorphin expression is focally and neuronally restricted and release is dependent on high‐frequency stimulation, as it occurs at the onset of seizures. The novel format of “release on demand” dynorphin delivery is viewed as a key to prevent habituation and to minimize the risk of adverse effects, leading to long‐term suppression of seizures and of their devastating sequel.https://doi.org/10.15252/emmm.201809963adeno‐associated viruslearningmemoryneuropeptideseizure |
| spellingShingle | Alexandra S Agostinho Mario Mietzsch Luca Zangrandi Iwona Kmiec Anna Mutti Larissa Kraus Pawel Fidzinski Ulf C Schneider Martin Holtkamp Regine Heilbronn Christoph Schwarzer Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy EMBO Molecular Medicine adeno‐associated virus learning memory neuropeptide seizure |
| title | Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy |
| title_full | Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy |
| title_fullStr | Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy |
| title_full_unstemmed | Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy |
| title_short | Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy |
| title_sort | dynorphin based release on demand gene therapy for drug resistant temporal lobe epilepsy |
| topic | adeno‐associated virus learning memory neuropeptide seizure |
| url | https://doi.org/10.15252/emmm.201809963 |
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