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New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development
The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at lea...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10501930/ https://www.ncbi.nlm.nih.gov/pubmed/37603261 http://dx.doi.org/10.1007/s40263-023-01025-4 |
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author | Perucca, Emilio White, H. Steve Bialer, Meir |
author_facet | Perucca, Emilio White, H. Steve Bialer, Meir |
author_sort | Perucca, Emilio |
collection | PubMed |
description | The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at least in part by potentiating GABAergic transmission, there is an opportunity for further research aimed at developing more innovative GABA-targeting therapies. The present article summarises available evidence on a number of such treatments in clinical development. These can be broadly divided into three groups. The first group consists of positive allosteric modulators of GABA(A) receptors and includes Staccato(®) alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the α2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101. A second group comprises two drugs already marketed for non-neurological indications, which could be repurposed as treatments for seizure disorders. These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomised double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents and restoring the function of GABAergic interneurons, currently tested in a trial in patients with Dravet syndrome, and an adenoviral vector-based gene therapy (ETX-101) scheduled for investigation in Dravet syndrome. Another agent, a subcutaneously administered neuroactive peptide (NRP2945) that reportedly upregulates the expression of GABA(A) receptor α and β subunits is being investigated, with Lennox–Gastaut syndrome and other epilepsies as proposed indications. The diversity of the current pipeline underscores a strong interest in the GABA system as a target for new treatment development in epilepsy. To date, limited clinical data are available for these investigational treatments and further studies are required to assess their potential value in addressing unmet needs in epilepsy management. |
format | Online Article Text |
id | pubmed-10501930 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-105019302023-09-16 New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development Perucca, Emilio White, H. Steve Bialer, Meir CNS Drugs Review Article The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at least in part by potentiating GABAergic transmission, there is an opportunity for further research aimed at developing more innovative GABA-targeting therapies. The present article summarises available evidence on a number of such treatments in clinical development. These can be broadly divided into three groups. The first group consists of positive allosteric modulators of GABA(A) receptors and includes Staccato(®) alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the α2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101. A second group comprises two drugs already marketed for non-neurological indications, which could be repurposed as treatments for seizure disorders. These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomised double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents and restoring the function of GABAergic interneurons, currently tested in a trial in patients with Dravet syndrome, and an adenoviral vector-based gene therapy (ETX-101) scheduled for investigation in Dravet syndrome. Another agent, a subcutaneously administered neuroactive peptide (NRP2945) that reportedly upregulates the expression of GABA(A) receptor α and β subunits is being investigated, with Lennox–Gastaut syndrome and other epilepsies as proposed indications. The diversity of the current pipeline underscores a strong interest in the GABA system as a target for new treatment development in epilepsy. To date, limited clinical data are available for these investigational treatments and further studies are required to assess their potential value in addressing unmet needs in epilepsy management. Springer International Publishing 2023-08-21 2023 /pmc/articles/PMC10501930/ /pubmed/37603261 http://dx.doi.org/10.1007/s40263-023-01025-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Review Article Perucca, Emilio White, H. Steve Bialer, Meir New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development |
title | New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development |
title_full | New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development |
title_fullStr | New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development |
title_full_unstemmed | New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development |
title_short | New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development |
title_sort | new gaba-targeting therapies for the treatment of seizures and epilepsy: ii. treatments in clinical development |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10501930/ https://www.ncbi.nlm.nih.gov/pubmed/37603261 http://dx.doi.org/10.1007/s40263-023-01025-4 |
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