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Development of an antiseizure drug screening platform for Dravet syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program

OBJECTIVE: Dravet syndrome (DS) is a rare but catastrophic genetic epilepsy, with 80% of patients carrying a mutation in the SCN1A gene. Currently, no antiseizure drug (ASD) exists that adequately controls seizures. In the clinic, individuals with DS often present first with a febrile seizure and, s...

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Autores principales: Pernici, Chelsea D., Mensah, Jeffrey A., Dahle, E. Jill, Johnson, Kristina J., Handy, Laura, Buxton, Lauren, Smith, Misty D., West, Peter J., Metcalf, Cameron S., Wilcox, Karen S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360068/
https://www.ncbi.nlm.nih.gov/pubmed/34002394
http://dx.doi.org/10.1111/epi.16925
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author Pernici, Chelsea D.
Mensah, Jeffrey A.
Dahle, E. Jill
Johnson, Kristina J.
Handy, Laura
Buxton, Lauren
Smith, Misty D.
West, Peter J.
Metcalf, Cameron S.
Wilcox, Karen S.
author_facet Pernici, Chelsea D.
Mensah, Jeffrey A.
Dahle, E. Jill
Johnson, Kristina J.
Handy, Laura
Buxton, Lauren
Smith, Misty D.
West, Peter J.
Metcalf, Cameron S.
Wilcox, Karen S.
author_sort Pernici, Chelsea D.
collection PubMed
description OBJECTIVE: Dravet syndrome (DS) is a rare but catastrophic genetic epilepsy, with 80% of patients carrying a mutation in the SCN1A gene. Currently, no antiseizure drug (ASD) exists that adequately controls seizures. In the clinic, individuals with DS often present first with a febrile seizure and, subsequently, generalized tonic‐clonic seizures that can continue throughout life. To facilitate the development of ASDs for DS, the contract site of the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) has evaluated a mouse model of DS using the conditional knock‐in Scn1a(A1783V/WT) mouse. METHODS: Survival rates and temperature thresholds for Scn1a(A1783V/WT) were determined. Prototype ASDs were administered via intraperitoneal injections at the time‐to‐peak effect, which was previously determined, prior to the induction of hyperthermia‐induced seizures. ASDs were considered effective if they significantly increased the temperature at which Scn1a(A1783V/WT) mice had seizures. RESULTS: Approximately 50% of Scn1a(A1783V/WT) survive to adulthood and all have hyperthermia‐induced seizures. The results suggest that hyperthermia‐induced seizures in this model of DS are highly refractory to a battery of ASDs. Exceptions were clobazam, tiagabine, levetiracetam, and the combination of clobazam and valproic acid with add‐on stiripentol, which elevated seizure thresholds. SIGNIFICANCE: Overall, the data demonstrate that the proposed model for DS is suitable for screening novel compounds for the ability to block hyperthermia‐induced seizures and that heterozygous mice can be evaluated repeatedly over the course of several weeks, allowing for higher throughput screening.
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spelling pubmed-83600682021-08-17 Development of an antiseizure drug screening platform for Dravet syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program Pernici, Chelsea D. Mensah, Jeffrey A. Dahle, E. Jill Johnson, Kristina J. Handy, Laura Buxton, Lauren Smith, Misty D. West, Peter J. Metcalf, Cameron S. Wilcox, Karen S. Epilepsia Full‐length Original Research OBJECTIVE: Dravet syndrome (DS) is a rare but catastrophic genetic epilepsy, with 80% of patients carrying a mutation in the SCN1A gene. Currently, no antiseizure drug (ASD) exists that adequately controls seizures. In the clinic, individuals with DS often present first with a febrile seizure and, subsequently, generalized tonic‐clonic seizures that can continue throughout life. To facilitate the development of ASDs for DS, the contract site of the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) has evaluated a mouse model of DS using the conditional knock‐in Scn1a(A1783V/WT) mouse. METHODS: Survival rates and temperature thresholds for Scn1a(A1783V/WT) were determined. Prototype ASDs were administered via intraperitoneal injections at the time‐to‐peak effect, which was previously determined, prior to the induction of hyperthermia‐induced seizures. ASDs were considered effective if they significantly increased the temperature at which Scn1a(A1783V/WT) mice had seizures. RESULTS: Approximately 50% of Scn1a(A1783V/WT) survive to adulthood and all have hyperthermia‐induced seizures. The results suggest that hyperthermia‐induced seizures in this model of DS are highly refractory to a battery of ASDs. Exceptions were clobazam, tiagabine, levetiracetam, and the combination of clobazam and valproic acid with add‐on stiripentol, which elevated seizure thresholds. SIGNIFICANCE: Overall, the data demonstrate that the proposed model for DS is suitable for screening novel compounds for the ability to block hyperthermia‐induced seizures and that heterozygous mice can be evaluated repeatedly over the course of several weeks, allowing for higher throughput screening. John Wiley and Sons Inc. 2021-05-17 2021-07 /pmc/articles/PMC8360068/ /pubmed/34002394 http://dx.doi.org/10.1111/epi.16925 Text en © 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Full‐length Original Research
Pernici, Chelsea D.
Mensah, Jeffrey A.
Dahle, E. Jill
Johnson, Kristina J.
Handy, Laura
Buxton, Lauren
Smith, Misty D.
West, Peter J.
Metcalf, Cameron S.
Wilcox, Karen S.
Development of an antiseizure drug screening platform for Dravet syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program
title Development of an antiseizure drug screening platform for Dravet syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program
title_full Development of an antiseizure drug screening platform for Dravet syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program
title_fullStr Development of an antiseizure drug screening platform for Dravet syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program
title_full_unstemmed Development of an antiseizure drug screening platform for Dravet syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program
title_short Development of an antiseizure drug screening platform for Dravet syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program
title_sort development of an antiseizure drug screening platform for dravet syndrome at the ninds contract site for the epilepsy therapy screening program
topic Full‐length Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360068/
https://www.ncbi.nlm.nih.gov/pubmed/34002394
http://dx.doi.org/10.1111/epi.16925
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