Voltage-gated sodium channels in excitable cells as drug targets

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Language: Английский

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Gene-replacement therapy in neurodevelopmental disorders: progress and challenges

Journal of Clinical Investigation, Journal Year: 2025, Volume and Issue: 135(3)

Published: Feb. 2, 2025

Heterozygous loss-of-function variants in the SLC6A1 gene, encoding GAT1, which is main GABA transporter brain, lead to a broad spectrum of neuropsychiatric and neurodevelopmental disorders including epilepsy, developmental delay, intellectual disability, autism. Gene-replacement strategies involving adeno-associated viruses (AAV) require delivery genes specific types neurons or areas likely during certain time points. In this issue JCI, Guo colleagues from Gray lab evaluated two promoters, three injection modalities, various timing for replacement GAT1 via AAV type 9 heterozygous homozygous knockout mouse models. Intrathecal administration vectors containing either promoter at postnatal day 5 achieved high expression was best tolerated approach. Notably, gene-replacement therapy failed later disease stages, suggesting importance early gene reconstitution confirming metabolism brain development.

Language: Английский

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Cannabinoid treatment for the symptoms of autism spectrum disorder

Expert Opinion on Emerging Drugs, Journal Year: 2024, Volume and Issue: 29(1), P. 65 - 79

Published: Jan. 2, 2024

Introduction Autism spectrum disorder (ASD) is a neurodevelopmental affecting approximately 3% of school-age children. The core symptoms are deficits in social communication and restricted repetitive patterns behavior. Associated problems cognition, language, behavior, sleep mood prevalent. Currently, no established pharmacological treatment exists for ASD symptoms. Risperidone aripiprazole used to manage associated irritability, but their effectiveness limited adverse events common.

Language: Английский

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The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives

The Lancet Child & Adolescent Health, Journal Year: 2024, Volume and Issue: 8(11), P. 821 - 834

Published: Oct. 16, 2024

Language: Английский

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Steps to Improve Precision Medicine in Epilepsy

Molecular Diagnosis & Therapy, Journal Year: 2023, Volume and Issue: 27(6), P. 661 - 672

Published: Sept. 27, 2023

Precision medicine is an old concept, but it not widely applied across human health conditions as yet. Numerous attempts have been made to apply precision in epilepsy, this has based on a better understanding of aetiological mechanisms and deconstructing disease into multiple biological subsets. The scope provide effective strategies for treating individual patients with specific agent(s) that are likely work best the causal make-up. We overview main applications including current limitations pitfalls, propose potential implementation achieve higher rate success patient care. Such include establishing definition its outcomes; learning from past experiences, failures other fields (e.g. oncology); using appropriate drug repurposing versus traditional discovery process); adequate methods assess efficacy randomised controlled trials alternative trial designs). Although progress diagnostic techniques now allows comprehensive characterisation each epilepsy condition molecular, biological, structural clinical perspective, there remain challenges integration data practice domain.

Language: Английский

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Recent advances and current status of gene therapy for epilepsy

World Journal of Pediatrics, Journal Year: 2024, Volume and Issue: 20(11), P. 1115 - 1137

Published: Oct. 12, 2024

Language: Английский

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Regulatory Elements for Gene Therapy of Epilepsy

Cells, Journal Year: 2025, Volume and Issue: 14(3), P. 236 - 236

Published: Feb. 6, 2025

The problem of drug resistance in epilepsy means that many cases, a surgical treatment may be advised. But this is only possible if there an epileptic focus, and resective brain surgery have adverse side effects. One the promising alternatives gene therapy, which allows targeted expression therapeutic genes different regions, even specific cell types. In review, we provide detailed explanations some key terms related to genetic engineering, describe various regulatory elements already been used development approaches treating using viral vectors. We compare few universal promoters for their strength duration transgene expression, our description cell-specific promoters, focus on driving glutamatergic neurons, GABAergic neurons astrocytes. also explore enhancers other cis-regulatory currently vectors consider future perspectives state-of-the-art technologies designing new, stronger more elements. Gene therapy has multiple advantages should become common future, but still lot study invent field.

Language: Английский

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Utility of adenoviral vectors in animal models of human disease: Genetic diseases

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 727 - 753

Published: Jan. 1, 2025

Language: Английский

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AAV-mediated interneuron-specific gene replacement for Dravet syndrome

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 15, 2023

Abstract Dravet syndrome (DS) is a devastating developmental epileptic encephalopathy marked by treatment-resistant seizures, delay, intellectual disability, motor deficits, and 10-20% rate of premature death. Most DS patients harbor loss-of-function mutations in one copy SCN1A , which has been associated with inhibitory neuron dysfunction. Here we developed an interneuron-targeting AAV human gene replacement therapy using cell class-specific enhancers. We generated split-intein fusion form to circumvent packaging limitations deliver via dual vector approach These constructs produced full-length Na V 1.1 protein functional sodium channels HEK293 cells brain vivo . After these vectors into enhancer-AAVs administering mice, immunohistochemical analyses showed telencephalic GABAergic interneuron-specific dose-dependent transgene biodistribution. conferred strong protection against postnatal mortality seizures two mouse models carrying independent alleles Scn1a, at research sites, supporting the robustness this approach. No or toxicity was observed wild-type mice injected single expressing either N-terminal C-terminal halves system targeting interneurons. In contrast, nonselective neuronal less rescue presented substantial preweaning lethality. findings demonstrate proof-of-concept that AAV-mediated sufficient for significant suggest it could be effective therapeutic DS.

Language: Английский

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Gene therapy for Dravet syndrome: promises and impact on disease trigger and secondary modifications

Rare Disease and Orphan Drugs Journal, Journal Year: 2024, Volume and Issue: 3(3)

Published: July 9, 2024

Dravet syndrome is a severe epileptic that begins during the first year of life otherwise healthy babies. Over years, seizure burden changes, and pathology evolves in strong association with behavioral alterations, including cognitive delay autistic traits. Initially, this aspect was considered direct consequence epilepsy severity, DS defined as an encephalopathy. Increasing evidence suggests these two aspects disease, impairment, might not be so strictly connected. mostly caused by heterozygous loss-of-function mutations SCN1A gene, which encodes for alpha-subunit voltage-gated sodium channel Nav1.1, responsible GABAergic interneuron excitability. Interneuron dysfunction evident at symptom onset murine models, but their activity appears to recover chronic phase when series secondary modifications arise likely drive phenotype. Given genetic basis disease clear, innovative therapies based on restoration sufficient expression levels Nav1.1 re-establish functional neuronal are being developed. In work, we review such therapeutic approaches, specific focus existing ability address only also modifications.

Language: Английский

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