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.

项目概要/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患有药物性疾病。耐药性，强调了替代疗法的必要性，这是发展疾病的最大挑战之一。修改疗法是对启动和治疗背后的潜在机制的有限了解我们建议开发一种针对齿状回的新型转化基因疗法。（DG）颗粒细胞，已被证明可以充当癫痫门控我们将利用特定的启动子。 DG颗粒细胞，Prospero相关同源盒1（Prox-1），选择性表达抑制性DREADD， hM4D(Gi)，在这些细胞中，我们发现这种具有高转化潜力的新型基因疗法将。有效抑制海马内红藻氨酸 (IHKA) 小鼠模型的自发性癫痫发作我们将首先开发并测试截短的 Prox-1 的敏感性和特异性。然后我们将检查 Prox-1::hM4D(Gi)-YFP 病毒载体在中的功效。抑制 DG 颗粒细胞并抑制 IHKA 小鼠癫痫模型中的慢性癫痫发作，同时还测试记忆效应（目标 2）。开发有效且高度可转化的疗法可以帮助我们更好地进行治疗。了解癫痫发作期间的作用机制，并改善耐药患者的治疗除了在癫痫方面的用途外，Prox1 驱动的表达载体还可能具有潜在的应用。阿尔茨海默病和神经精神疾病以及淋巴和癌症研究。