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The development of gene therapeutic approaches to suppress cerebral inflammation in dementia

抑制痴呆症脑炎症的基因治疗方法的发展

基本信息

批准号：
10524978
负责人：
Robert Anthony Marr
金额：
$ 42.9万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524978
关键词：
Adaptor Signaling Protein Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease therapy Amyloid beta-Protein Amyloidosis Animal Model Apolipoproteins B Area Behavior Binding Sites Biological Products Blood Blood - brain barrier anatomy Brain CASP1 gene Cell membrane Cells Cerebrum Clinic Clinical Trials Complex Dementia Dependovirus Development Disease Disease Pathway Dominant-Negative Mutation Elderly Engineering Failure Family Future Gene Delivery Gene Transfer Genes Inflammasome Inflammation Inflammatory Injections Interleukin-1 beta Interleukin-18 Knock-out Learning Link Liver Low Density Lipoprotein Receptor Measures Membrane Memory Methods Modeling Nerve Degeneration Neuraxis Pathology Pathway interactions Peptides Peripheral Population Procedures Proteins Rattus Retina Risk Factors Rodent Model Route Societies Stream Synapses System Technology Transfer Testing Therapeutic Agents Therapeutic Intervention Toxic effect Transgenes Transgenic Mice Transgenic Organisms Treatment Efficacy Viral Work adeno-associated viral vector astrogliosis clinically relevant comparison intervention cytokine demographics drug development gene delivery system gene therapy genetic inhibitor inhibitor intravenous injection marenostrin morris water maze neurochemistry novel novel therapeutic intervention object recognition preclinical study sensor tau-1 therapeutic gene therapeutically effective trafficking transgene expression transgenic model of alzheimer disease transport inhibitor vector ventricular system

项目摘要

There is an urgent need for the development of new and effective therapeutic approaches to Alzheimer’s disease (AD). The field of gene therapy has progressed significantly in the last 10 years and is beginning to enter the clinic for disease treatment. Gene transfer approaches have the advantage of being more targeted to specific pathways and require far fewer interventions compared to more traditional approaches. In the AD field, it has become clear that inflammation is a key component contributing to AD pathology. One major route for inflammation is through activation of inflammasomes, sensors of cellular insults. Therefore, we propose the development of gene transfer approaches to inhibit inflammasome function. This will be done through the use of a brain administered dominant-negative (DN) inhibitor of the inflammasome complex (Aim 1) or through the use of a peripherally delivered brain-targeted DN inhibitor of the inflammasome complex (Aim 2). Adeno- associated viral (AAV) vectors will be used to facilitate DN inhibitor gene expression as they provide an efficient and safe vector system. We will use a rat transgenic model of AD-like amyloidosis to test these approaches and assess learning/memory in addition to neurochemical and immunohistological measure associated with AD. This proposal will explore novel therapeutic approaches to AD through targeting a key inflammatory disease pathway in a relevant animal model.

迫切需要开发新的有效的阿尔茨海默病治疗方法疾病（AD）。基因治疗领域在过去 10 年中取得了显着进展，并开始进入诊所进行疾病治疗。基因转移方法的优点是更有针对性与更传统的方法相比，该方法具有特定的途径，并且需要更少的干预措施。在AD领域，很明显，炎症是 AD 病理学的一个关键组成部分。一条主要路线为炎症是通过激活炎症小体（细胞损伤的传感器）来实现的。因此，我们建议开发基因转移方法来抑制炎症小体功能。这将通过使用来完成大脑给予炎性体复合物的显性失活（DN）抑制剂（目标 1）或通过使用外周递送的脑靶向炎症小体复合物 DN 抑制剂（目标 2）。腺苷- 相关病毒 (AAV) 载体将用于促进 DN 抑制剂基因表达，因为它们提供了高效、安全的载体系统。我们将使用 AD 样淀粉样变性大鼠转基因模型来测试这些除了神经化学和免疫组织学测量之外，方法和评估学习/记忆与AD有关。该提案将通过针对关键的关键点来探索 AD 的新治疗方法。相关动物模型中的炎症性疾病途径。