Development and Validation of a Transgenic Rabbit Model of Dravet Syndrome
Dravet 综合征转基因兔模型的开发和验证
基本信息
- 批准号:10574719
- 负责人:
- 金额:$ 37.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:Action PotentialsAgeAnimal GeneticsAnimal ModelAnimalsAntisense OligonucleotidesApneaArrhythmiaAutonomic DysfunctionBehavioralBiological MarkersBrainCRISPR/Cas technologyCalciumCardiacCardiac MyocytesCardiovascular systemCause of DeathCellsCessation of lifeClinicalComplexDataDevelopmentDissectionDrug CombinationsEpilepsyFrequenciesFutureGeneralized seizuresGenesGeneticGenetic ModelsGoalsHeartHumanIncidenceKnowledgeLinkMichiganModelingMusNeuronsNew ZealandOrganismOryctolagus cuniculusPatientsPharmaceutical PreparationsPhasePhenotypePhysiologyRattusRiskRodentRoleSCN1A proteinSCN8A geneSeizuresSodiumSodium ChannelTestingTissuesTransgenic MiceTransgenic OrganismsTranslatingTranslational ResearchUniversitiesValidationVariantVideo RecordingWorkclinical diagnosisclobazamcohortdensitydravet syndromeeffective therapyepileptic encephalopathiesgain of functiongene therapyheart innervationhuman diseasehuman old age (65+)induced pluripotent stem cellinsightloss of functionmouse modelnerve supplynovel markernovel therapeutic interventionprematurepreventrespiratoryrisk variantstem cell modelsuccesssudden unexpected death in epilepsytranslational modeltranslational therapeuticstwo-dimensionalvoltage
项目摘要
ABSTRACT
Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of death in patients with epilepsy. SUDEP
mechanisms are not understood, although there is evidence to implicate apnea, autonomic dysfunction, and
cardiac arrhythmias. Our work in mice led to the hypothesis that cardiac arrhythmias contribute to the mechanism
of SUDEP in channelopathy-linked genetic epilepsies. We demonstrated altered cardiac myocyte (CM) ionic
currents, calcium handling, and action potentials (APs), as well as cardiac arrhythmias in mouse models of
SCN1A-, SCN8A-, and SCN1B-linked developmental and epileptic encephalopathy (DEE). We showed that
induced pluripotent stem cell (iPSC)-derived CMs from Dravet syndrome (DS) patients have substrates for
arrhythmias. Importantly, no animal or iPSC model can completely replicate the human DS phenotype. Because
mouse and human cardiac APs are very different, we used human iPSC-CM models to investigate cell
autonomous effects of SCN1A haploinsufficiency. However, cells in 2-dimensional culture cannot replicate
complex cardiac tissues, cardiovascular changes, or cardiac innervation. Here, we will develop and validate a
large animal model in which the role of cardiac arrhythmias, in addition to seizures, in SUDEP can be
investigated. Rabbits closely replicate the human cardiac AP and provide a complete organism to translate to
the clinical setting. Our objective is to develop and validate a transgenic rabbit model of SCN1A-linked DS. We
generated a New Zealand White (NZW) rabbit Scn1a deletion model using CRISPR-Cas9 gene editing.
However, NZW Scn1a+/- rabbits showed neither seizures nor cardiac arrhythmia. We later found that F1: NZW x
Dutch Belted Scn1a+/- rabbits have seizures, cardiac arrhythmia, and premature death. These exciting results
suggest that we may have generated the first transgenic large animal model of a DEE, although this model must
now be rigorously validated. If validated, this work will be a significant advance over currently available DS
models. R61 Phase Specific Aims: 1. To characterize seizure onset, seizure types, seizure frequency and
duration, and determine the rate of SUDEP in DS rabbits. 2. To characterize arrhythmia types, frequency, and
duration, whether arrhythmias occur independently of seizures, and whether cardiac arrhythmia is associated
with SUDEP in DS rabbits. R33 Phase Specific Aim: To validate the model using the ASO drug STK-001 or the
drug combination stiripentol + clobazam to reduce seizures and SUDEP. Establishing a genetic rabbit model of
DS will better inform the translatability of neuro-cardiac mechanisms of SUDEP to human disease.
摘要
癫痫猝死(SUDEP)是癫痫患者的主要死亡原因。SUDEP
机制尚不清楚,尽管有证据表明呼吸暂停、自主神经功能障碍和
心律失常。我们在小鼠身上的工作导致了心律失常与这一机制有关的假说
SUDEP在经络病连锁遗传性癫痫中的作用。我们证明了心肌细胞(CM)离子的改变
电流、钙离子处理和动作电位(AP),以及心律失常
SCN1A、SCN8A和SCN1B连锁的发育性和癫痫性脑病(DIE)。我们向大家展示了
Dravet综合征(DS)患者的诱导多能干细胞(IPSC)来源的CMS具有以下底物
心律不齐。重要的是,任何动物或IPSC模型都不能完全复制人类DS的表型。因为
小鼠和人类的心脏AP非常不同,我们使用人类IPSC-CM模型来研究细胞
SCN1A单倍体功能不全的自主效应。然而,二维培养中的细胞不能复制
复杂的心脏组织、心血管改变或心脏神经支配。在这里,我们将开发和验证
除癫痫发作外,心律失常在SUDEP中的作用可以是一种大型动物模型
调查过了。兔子紧密复制人类心脏AP,并提供一个完整的有机体来翻译
临床环境。我们的目标是建立和验证SCN1A连锁DS的转基因兔模型。我们
利用CRISPR-Cas9基因编辑技术建立新西兰白兔Scn1a缺失模型。
而NZW Scn1a+/-兔未出现惊厥和心律失常。后来我们发现F1:NZW x
荷兰腰带Scn1a+/-兔有癫痫发作、心律失常和过早死亡。这些令人兴奋的结果
这表明我们可能已经产生了第一个转基因的大型动物DIE模型,尽管这个模型必须
现在要进行严格的验证。如果得到验证,这项工作将比目前可用的DS有很大的进步
模特们。R61阶段的具体目标:1.表征癫痫发作、癫痫类型、癫痫发作频率和
持续时间,并测定DS兔SUDEP发生率。2.确定心律失常的类型、频率和
持续时间,心律失常是否独立于癫痫发作发生,以及心律失常是否相关
在DS兔体内应用SUDEP。R33阶段特定目标:使用ASO药物STK-001或
联合用药以减少癫痫发作和SUDEP。建立遗传性兔模型的研究
DS将更好地说明SUDEP的神经心脏机制对人类疾病的可译性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lori L. Isom其他文献
I. Cellular and molecular biology of sodium channel beta-subunits: therapeutic implications for pain?
I. 钠通道 β 亚基的细胞和分子生物学:对疼痛的治疗意义?
- DOI:
- 发表时间:
2000 - 期刊:
- 影响因子:0
- 作者:
Lori L. Isom - 通讯作者:
Lori L. Isom
Na+ channel subunits and Ig domains
钠离子通道亚单位和免疫球蛋白结构域
- DOI:
10.1038/383307b0 - 发表时间:
1996-09-26 - 期刊:
- 影响因子:48.500
- 作者:
Lori L. Isom;William A. Catterall - 通讯作者:
William A. Catterall
Modulation of Kv1 Voltage-Gated Potassium Channels by Sodium Channel Beta Subunits
- DOI:
10.1016/j.bpj.2011.11.3733 - 发表时间:
2012-01-31 - 期刊:
- 影响因子:
- 作者:
Hai M. Nguyen;Jeffrey D. Calhoun;Lori L. Isom;Alan L. Goldin;George K. Chandy - 通讯作者:
George K. Chandy
Dramatic Improvement in Seizures With Phenytoin Treatment in an Individual With Refractory Epilepsy and a <em>SCN1B</em> Variant
- DOI:
10.1016/j.pediatrneurol.2020.03.012 - 发表时间:
2020-07-01 - 期刊:
- 影响因子:
- 作者:
Louis T. Dang;Shane C. Quinonez;Bridget R. Becka;Lori L. Isom;Sucheta M. Joshi - 通讯作者:
Sucheta M. Joshi
Ontology accelerates few-shot learning capability of large language model: A study in extraction of drug efficacy in a rare pediatric epilepsy
本体论加速大型语言模型的少样本学习能力:一项关于罕见儿童癫痫药物疗效提取的研究
- DOI:
10.1016/j.ijmedinf.2025.105942 - 发表时间:
2025-09-01 - 期刊:
- 影响因子:4.100
- 作者:
Pedram Golnari;Katrina Prantzalos;Veronica Hood;Mary Anne Meskis;Lori L. Isom;Karen Wilcox;Jack M. Parent;Dennis Lal;Samden D. Lhatoo;Howard P. Goodkin;Elaine C. Wirrell;Kelly G. Knupp;Manisha Patel;Jeffrey A. Loeb;Joseph E. Sullivan;Lauren Harte-Hargrove;Brandy E. Fureman;Jeffrey Buchhalter;Satya S. Sahoo - 通讯作者:
Satya S. Sahoo
Lori L. Isom的其他文献
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{{ truncateString('Lori L. Isom', 18)}}的其他基金
Interdepartmental Training in Pharmacological Sciences
药理学科学跨部门培训
- 批准号:
10616678 - 财政年份:2021
- 资助金额:
$ 37.21万 - 项目类别:
Interdepartmental Training in Pharmacological Sciences
药理学科学跨部门培训
- 批准号:
10397983 - 财政年份:2021
- 资助金额:
$ 37.21万 - 项目类别:
Cardiac Mechanisms of Sudden Unexpected Death in Epilepsy
癫痫猝死的心脏机制
- 批准号:
10454393 - 财政年份:2020
- 资助金额:
$ 37.21万 - 项目类别:
Epilepsy Multiplatform Variant Prediction (EpiMVP) - Admin Core
癫痫多平台变异预测 (EpiMVP) - 管理核心
- 批准号:
10670354 - 财政年份:2020
- 资助金额:
$ 37.21万 - 项目类别:
Development of a Rabbit Model of SCN1A-linked Dravet Syndrome
SCN1A 相关 Dravet 综合征兔模型的开发
- 批准号:
10062010 - 财政年份:2020
- 资助金额:
$ 37.21万 - 项目类别:
Cardiac Mechanisms of Sudden Unexpected Death in Epilepsy
癫痫猝死的心脏机制
- 批准号:
10661021 - 财政年份:2020
- 资助金额:
$ 37.21万 - 项目类别:
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