{"doi":"10.1172/jci182584","title":"Neonatal but not juvenile gene therapy reduces seizures and prolongs lifespan in SCN1B–Dravet syndrome mice","abstract":"Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) that begins in the first year of life. While most cases of DS are caused by variants in SCN1A, variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are also linked to DS or to the more severe early infantile DEE. Both disorders fall under the OMIM term DEE52. Scn1b-null mice model DEE52, with spontaneous generalized seizures and death in 100% of animals in the third postnatal week. Scn1b-null cortical parvalbumin-positive interneurons and pyramidal neurons are hypoexcitable. The goal of this study was to develop a proof-of-principle gene replacement strategy for DEE52. We tested an adeno-associated viral vector encoding β1 subunit cDNA (AAV-Navβ1) in Scn1b-null mice. We demonstrated that AAV-Navβ1 drives β1 protein expression in excitatory and inhibitory neurons in mouse brains. Bilateral intracerebroventricular administration of AAV-Navβ1 in Scn1b-null mice at postnatal day 2 (P2), but not at P10, reduced spontaneous seizure severity and duration, prolonged lifespan, prevented hyperthermia-induced seizures, and restored cortical neuron excitability. AAV-Navβ1 administration to WT mice resulted in β1 overexpression in brain but no obvious adverse effects. This work lays the foundation for future development of a gene therapeutic strategy for patients with SCN1B-linked DEE.","journal":"Journal of Clinical Investigation","year":2025,"id":516936,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9412,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":286744,"name":"Yukun Yuan","orcid":"0000-0002-6213-4448","position":1,"is_corresponding":false},{"id":1030846,"name":"Heather A. O’Malley","orcid":"0000-0003-0204-7841","position":2,"is_corresponding":false},{"id":1383292,"name":"Robert Duba-Kiss","orcid":null,"position":3,"is_corresponding":false},{"id":1081001,"name":"Yan Chen","orcid":"0000-0002-1646-6935","position":4,"is_corresponding":false},{"id":1081457,"name":"Karl Habig","orcid":null,"position":5,"is_corresponding":false},{"id":1383293,"name":"Yosuke Niibori","orcid":null,"position":6,"is_corresponding":false},{"id":294699,"name":"Samantha L. Hodges","orcid":"0000-0002-1728-9539","position":7,"is_corresponding":false},{"id":1382832,"name":"David R. Hampson","orcid":"0000-0002-2102-2554","position":8,"is_corresponding":false},{"id":286747,"name":"Lori L. Isom","orcid":"0000-0002-9479-6729","position":9,"is_corresponding":false},{"id":1030845,"name":"Chunling Chen","orcid":"0000-0001-8381-8710","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:48:54.768083Z","pmid":"39847501","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}