Development and validation of a viral vector for targeted inhibition of DG granule cells

用于靶向抑制 DG 颗粒细胞的病毒载体的开发和验证

基本信息

批准号：
10648833
负责人：
ROBERT E GROSS
金额：
$ 23.48万
依托单位：
EMORY UNIVERSITY
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：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648833
关键词：
Ablation Adult Alternative Therapies Alzheimer&apos s Disease Anticonvulsants Brain Cells Cessation of life Chronic Clinical Trials Development Disease Disease Progression Drug resistance Early Intervention Enhancers Epilepsy Epileptogenesis Equilibrium Excision Face Frequencies Future Genes Genetic Genomic Segment Glutamates Goals Hippocampal Formation Hippocampus Homeobox Homeodomain Proteins Human In Vitro Intervention Intractable Epilepsy Kainic Acid Light Lymphatic Research Medial Memory Modeling Molecular Neurobiology Morphology Mus Neurons Operative Surgical Procedures Opsin Organism Outcome Pathology Patients Plasmids Play Population Primates Protein Truncation Proteins Pyramidal Cells Recurrence Regulation Regulatory Element Resistance Risk Rodent Seizures Sensitivity and Specificity Signal Pathway Temporal Lobe Temporal Lobe Epilepsy Testing Therapeutic Transgenic Mice Transgenic Organisms Validation Viral Vector Wild Type Mouse Work adeno-associated viral vector anticancer research axonal sprouting comparative efficacy dentate gyrus designer receptors exclusively activated by designer drugs effectiveness testing efficacy evaluation expression vector gene therapy granule cell improved in vivo inhibitory neuron innovation mouse model nervous system disorder neuropsychiatric disorder neuroregulation nonhuman primate novel novel strategies prevent promoter receptor selective expression side effect synthetic biology targeted treatment translational potential translational therapeutics

项目摘要

PROJECT SUMMARY/ABSTRACT Epilepsy is one of the most common neurological disorders. Approximately one third of patients are drug- resistant, underscoring the need for alternative therapies. One of the biggest challenges to developing disease- modifying therapies is the limited understanding of the underlying mechanisms behind the initiation and propagation of seizures. We propose to develop a novel, translational gene therapy that targets dentate gyrus (DG) granule cells, which have been shown to act as a seizure gate. We will make use of a promoter specific to DG granule cells, Prospero-related homeobox 1 (Prox-1), to selectively express the inhibitory DREADD, hM4D(Gi), in these cells. We hypothesize that this novel gene therapy with high translational potential will effectively suppress spontaneously recurring seizures in the intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy. We will first develop and test the sensitivity and specificity of a truncated Prox-1 promoter and enhancers (Aim1). We then will examine the efficacy of a Prox-1::hM4D(Gi)-YFP viral vector in inhibiting DG granule cells and suppressing chronic seizures in the IHKA mouse model of epilepsy, while also testing memory effects (Aim 2). Development of an effective and highly translatable therapy can help us better understand the mechanisms at play during seizures, as well as improve treatment in patients with drug-resistant epilepsy. In addition to its utility in epilepsy, a Prox1-driven expression vector could have potential applications in Alzheimer’s disease and neuropsychiatric disorders as well as in lymphatic and cancer research.

项目摘要/摘要癫痫是最常见的神经系统疾病之一。大约三分之一的患者是药物抵抗力，强调需要替代疗法。发展疾病的最大挑战之一 - 修改疗法是对倡议背后的基本机制的有限理解和癫痫发作的传播。我们建议开发一种针对齿状回的新颖，翻译的基因疗法（DG）颗粒细胞，已证明充当癫痫门。我们将利用特定于 DG颗粒细胞，与Prospero相关的同型ox 1（Prox-1），有选择地表达抑制性dreadd，在这些细胞中，HM4D（GI）。我们假设这种具有高转化潜力的新型基因疗法将有效地抑制在海马内海藻酸（IHKA）小鼠模型中自发癫痫发作临时叶癫痫。我们将首先发展和测试截短的Prox-1的灵敏度和特异性发起人和增强剂（AIM1）。然后，我们将检查Prox-1 :: HM4D（GI）-YFP病毒载体的效率抑制DG颗粒细胞并抑制癫痫IHKA小鼠模型中的慢性癫痫发作，同时也测试记忆效果（AIM 2）。开发有效且高度可翻译的疗法可以帮助我们更好了解癫痫发作期间发挥作用的机制，以及耐药患者的改善治疗 epipodepsy。除了其在episodepsy中的效用外，Prox1驱动的表达向量还可以具有潜在的应用在阿尔茨海默氏病和神经精神疾病以及淋巴和癌症研究中。