In silico prediction and in vivo testing of promoters targeting GABAergic inhibitory neurons

Niibori, Yosuke; Duba-Kiss, Robert; Bruder, Joseph T.; Smith, Jared B.; Hampson, David R.

doi:10.1016/j.omtm.2023.01.007

Cited by 3 publications

(2 citation statements)

References 42 publications

(62 reference statements)

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“…Although this article focused on investigational treatments for which clinical data are available, or likely to be available in the short term, preclinical research in this area is also very active. Drug candidates being investigated preclinically include, among others, novel GABA A receptor agonists and allosteric modulators [14,33,111], compounds targeting GABA B receptors [116,117], a highly potent inhibitor of GABA transaminase [118], a new class of selective NKCC1 inhibitors [82] and novel GABA-targeting viral vectors [119]. At the other extreme of the development spectrum, clinical studies are ongoing to assess novel applications of already marketed GABA-targeting ASMs.…”

Section: Discussionmentioning

confidence: 99%

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development

Perucca,

White,

Bialer

2023

CNS Drugs

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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.

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Section: Discussionmentioning

confidence: 99%

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development

Perucca,

White,

Bialer

2023

CNS Drugs

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“…For example, selectively attenuating glutamatergic projection neurons in the ventral claustrum through gene therapy may prevent seizure generalization or impaired awareness as previously discussed. Even developmental and epileptic encephalopathies such as Dravet syndrome may benefit from selective targeting of Nav1.1 parvalbumin neurons in the claustrum (Vormstein-Schneider et al, 2020;Niibori et al, 2023).…”

Section: A Case For Involvement Of the Claustrum In Impaired Awarenes...mentioning

confidence: 99%

Is there room in epilepsy for the claustrum?

Watson,

Meletti,

Mahavadi

et al. 2024

Front. Syst. Biol.

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The function of the claustrum and its role in neurological disorders remains a subject of interest in the field of neurology. Given the claustrum’s susceptibility to seizure-induced damage, there is speculation that it could serve as a node in a dysfunctional epileptic network. This perspective article aims to address a pivotal question: Does the claustrum play a role in epilepsy? Building upon existing literature, we propose the following hypotheses for the involvement of the claustrum in epilepsy: (1) Bilateral T2/FLAIR magnetic resonance imaging (MRI) hyperintensity of the claustrum after status epilepticus represents a radiological phenomenon that signifies inflammation-related epileptogenesis; (2) The ventral claustrum is synonymous with a brain area known as ‘area tempestas,’ an established epileptogenic center; (3) The ventral subsector of the claustrum facilitates seizure generalization/propagation through its connections with limbic and motor-related brain structures; (4) Disruption of claustrum connections during seizures might contribute to the loss of consciousness observed in impaired awareness seizures; (5) Targeting the claustrum therapeutically could be advantageous in seizures that arise from limbic foci. Together, evidence from both clinical case reports and animal studies identify a significant role for the ventral claustrum in the generation, propagation, and intractable nature of seizures in a subset of epilepsy syndromes.

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Genetic approaches to elucidating cortical and hippocampal GABAergic interneuron diversity

Machold,

Rudy

2024

Front. Cell. Neurosci.

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GABAergic interneurons (INs) in the mammalian forebrain represent a diverse population of cells that provide specialized forms of local inhibition to regulate neural circuit activity. Over the last few decades, the development of a palette of genetic tools along with the generation of single-cell transcriptomic data has begun to reveal the molecular basis of IN diversity, thereby providing deep insights into how different IN subtypes function in the forebrain. In this review, we outline the emerging picture of cortical and hippocampal IN speciation as defined by transcriptomics and developmental origin and summarize the genetic strategies that have been utilized to target specific IN subtypes, along with the technical considerations inherent to each approach. Collectively, these methods have greatly facilitated our understanding of how IN subtypes regulate forebrain circuitry via cell type and compartment-specific inhibition and thus have illuminated a path toward potential therapeutic interventions for a variety of neurocognitive disorders.

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In silico prediction and in vivo testing of promoters targeting GABAergic inhibitory neurons

Cited by 3 publications

References 42 publications

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development

Is there room in epilepsy for the claustrum?

Genetic approaches to elucidating cortical and hippocampal GABAergic interneuron diversity

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