AAV9-mediated targeting of natural antisense transcript as a novel treatment for Dravet Syndrome DOI Creative Commons
Juan Antinao Díaz, Ellie Chilcott, Amanda Almacellas‐Barbanoj

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 28, 2024

Abstract Dravet syndrome (DS) is a severe childhood onset developmental and epileptic encephalopathy which leads to life-long disability. Symptoms usually manifest in the first year of life include prolonged seizures, delay intellectual DS patients have an increased mortality rate, including sudden unexpected death epilepsy (SUDEP). Approximately 90% carry heterozygous loss-of-function mutation SCN1A gene, encodes voltage-gated sodium ion channel, Na V 1.1. The 1.1 channel expressed brain at lower level, heart. Previous studies identified long non-coding RNA (lncRNA) specifically downregulates gene expression. This natural antisense transcript (NAT) can be modulated by AntagoNATs, small synthetic oligonucleotides developed inhibit NAT function. In mouse model, AntagoNATs were shown modulate Scn1a expression targeting NAT, improving seizure frequency after repeated administration. Here, we novel incorporated these into clinically relevant adeno-associated virus serotype 9 (AAV9) therapy vector, test model ( +/- ) provide one-off treatment approach. Eighteen tested vitro ; from best performing candidates, selected two AntagoNAT sequences (K & H) for vivo testing as they had highest homology (90%) human NAT. We administered both vectors newborn mice via intracerebroventricular (ICV) intravenous (IV) injection target AAV9-AntagoNAT-H significantly survival, decreased febrile seizures reduced spontaneous compared PBS control group. When P14 ICV IV injection, survival. this proof-of-concept study, demonstrated time delivery technology AAV9 vector thus offering possibility one-time patients.

Language: Английский

Voltage-gated sodium channels in excitable cells as drug targets DOI
Matthew Alsaloum, Sulayman D. Dib‐Hajj, Dana A. Page

et al.

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

Published: Feb. 3, 2025

Language: Английский

Citations

4
Gene-replacement therapy in neurodevelopmental disorders: progress and challenges DOI Creative Commons
Holger Lerche, Ulrike B. S. Hedrich, Thomas V. Wuttke

et al.

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

Citations

1
The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives DOI
Nicola Specchio, Marina Trivisano, Eleonora Aronica

et al.

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

Published: Oct. 16, 2024

Language: Английский

Citations

7
Cannabinoid treatment for the symptoms of autism spectrum disorder DOI
Adi Aran,

Dalit Cayam Rand

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

Citations

6
Steps to Improve Precision Medicine in Epilepsy DOI Creative Commons
Simona Balestrini, Davide Mei, Sanjay M. Sisodiya

et al.

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

Citations

12
Recent advances and current status of gene therapy for epilepsy DOI

Aojie Cai,

Kai Gao, Fan Zhang

et al.

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

Published: Oct. 12, 2024

Language: Английский

Citations

4
Regulatory Elements for Gene Therapy of Epilepsy DOI Creative Commons
Ekaterina Chesnokova, Natalia Bal, Ghofran Alhalabi

et al.

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

Citations

0
Utility of adenoviral vectors in animal models of human disease: Genetic diseases DOI
Rubén Hernández-Alcoceba

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

Published: Jan. 1, 2025

Language: Английский

Citations

0
AAV-mediated interneuron-specific gene replacement for Dravet syndrome DOI Open Access
John K. Mich,

Jiyun Ryu,

Aguan Wei

et al.

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

Citations

7
AAV-mediated Stambp gene replacement therapy rescues neurological defects in a mouse model of microcephaly-capillary malformation syndrome DOI

Meixin Hu,

Jun Li,

Jingxin Deng

et al.

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(11), P. 4095 - 4107

Published: Aug. 23, 2024

Language: Английский

Citations

2