{"doi":"10.1101/2020.12.01.406470","title":"Development of an Antiseizure Drug Screening Platform for Dravet Syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program","abstract":"Summary Objective Dravet syndrome (DS) is a rare, but catastrophic genetic epilepsy, with 80% of patients with carrying a mutation in the SCN1A gene. Currently, no anti-seizure drug (ASD) exists that adequately controls seizures. Patients with DS often present clinically with a febrile seizure and generalized tonic-clonic seizures that continue throughout life. To facilitate the development of ASDs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has evaluated a mouse model of DS using the conditional knock-in Scn1a A1783V/WT mouse. Methods Survival rates and temperature thresholds for Scn1a A1783V/WT were determined. Prototype ASDs were administered via intraperitoneal injections at the time-to-peak effect, which was previously determined, prior to the induction of hyperthermia-induced seizures. Protection was determined if ASDs significantly increased the temperature at which Scn1a A1783V/WT mice seized. Results Approximately 50% of Scn1a A1783V/WT survive to adulthood and all have hyperthermia-induce seizures. The results suggest that hyperthermia-induced seizures in this model of DS are highly refractory to a battery of ASDs. Exceptions were clobazam, tiagabine, and the combination of clobazam and valproic acid with add-on stiripentol, which elevated seizure thresholds Significance Overall, the data demonstrate the proposed model for DS is suitable for screening novel compounds for the ability to block hyperthermia-induced seizures and heterozygous mice can be evaluated repeatedly over the course of several weeks, allowing for higher throughput screening. Key Points Scn1a A1783V/WT mice have a 50% survival rate and all have hyperthermia-induced seizures. Common DS treatments such as CLB and combinatorial therapy of CLB, VPA, and STP increase temperature thresholds in Scn1a A1783V/WT mice. Sodium channel blockers, such as CBZ and LTG, decrease temperature thresholds of Scn1a A1783V/WT mice as predicted. S cn1a A1783V/WT mice are highly pharmacoresitant to common ASDs The Scn1a A1783V/WT may be a useful preclinical drug screening platform for the treatment of DS.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":123170,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":565847,"name":"Jeffrey A. Mensah","orcid":"0000-0001-7026-9329","position":1,"is_corresponding":false},{"id":566541,"name":"E. Jill Dahle","orcid":null,"position":2,"is_corresponding":false},{"id":566542,"name":"Kristina Johnson","orcid":null,"position":3,"is_corresponding":false},{"id":566543,"name":"Laura Handy","orcid":null,"position":4,"is_corresponding":false},{"id":566544,"name":"Lauren Buxton","orcid":null,"position":5,"is_corresponding":false},{"id":479446,"name":"Misty D. Smith","orcid":"0000-0001-8198-722X","position":6,"is_corresponding":false},{"id":565848,"name":"Peter J. West","orcid":"0000-0002-5774-5180","position":7,"is_corresponding":false},{"id":454962,"name":"Cameron S. Metcalf","orcid":"0000-0002-1510-0405","position":8,"is_corresponding":false},{"id":454963,"name":"Karen S. Wilcox","orcid":"0000-0003-2660-8826","position":9,"is_corresponding":false},{"id":406140,"name":"Chelsea D. Pernici","orcid":"0000-0003-3531-7086","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-18T23:14:59.547352Z","pmid":null,"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":[]}