Drug repurposing for Alzheimer’s disease-related inflammation caused by a TBI

药物再利用，治疗 TBI 引起的阿尔茨海默病相关炎症

基本信息

批准号：
10590132
负责人：
ADAM D BACHSTETTER
金额：
$ 22.95万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2023-02-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10590132
关键词：
APP-PS1 Acceleration Acute Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk American Antibiotics Area Astrocytes Azithromycin Behavioral Behavioral Assay Biological Products Brain Brain Injuries Clinical Research Closed head injuries Cognitive Cognitive deficits Data Dementia Dose Drug Targeting Drug usage Elderly Environmental Risk Factor Evaluation Evaluation Research Exploratory/Developmental Grant FDA approved Failure Gliosis Goals Histopathology Immunosuppressive Agents Incidence Infection Inflammation Inflammatory Injury Kentucky Knock-in Mouse Microglia Modeling Nervous System Trauma Odds Ratio Outcome Pathology Patient-Focused Outcomes Pharmaceutical Preparations Phase Phenotype Population Populations at Risk Positioning Attribute Pre-Clinical Model Predisposition Property Prophylactic treatment Radial Recovery Research Resolution Risk Safety Speed Spinal cord injury Synapses TBI treatment TNF gene Testing Therapeutic Therapeutic Agents Time Traumatic Brain Injury Universities Wild Type Mouse Work aging brain amyloid pathology arm blood-brain barrier crossing cost disorder risk drug development drug discovery drug efficacy drug repurposing experience falls human old age (65+)immune modulating agents immunomodulatory therapies immunoregulation improved infection risk medical attention mild traumatic brain injury mouse model neuroinflammation neuropathology neuroprotection novel therapeutics pharmacokinetics and pharmacodynamics pre-clinical prevent primary endpoint research and development response tau Proteins therapeutic development therapeutic evaluation treatment duration water maze

项目摘要

PROJECT SUMMARY/ABSTRACT The CDC estimates that at least 200,000 older Americans (> 65 years) will have a traumatic brain injury (TBI) each year, primarily caused by a closed head injury (CHI) from a fall. The aged brain, with Alzheimer’s disease neuropathological changes, has significant reactive microglia and astrocytes and other markers of neuroinflammation. An acquired brain injury can further exacerbate this state of reactive gliosis and neuroinflammation. Alzheimer’s disease poses a significant therapeutic challenge, given that pathology can develop over decades. However, we believe that it is an obtainable therapeutic goal to prevent the worsening of neuroinflammation caused by an acquired brain injury in those at risk for developing Alzheimer’s disease . Control of neuroinflammation following the TBI in older adults is a promising avenue for improving patient outcomes. However, no drug has earned FDA approval for specific use in mild TBI. There is also limited evidence to guide the repurposing of FDA-approved drugs that target neuroinflammation for this unique population. Broad-spectrum immunosuppressants are not advisable and, while selective biologics (such as anti-TNF) are promising, they also come with the risk of increasing infection, which is problematic in an older adult population at risk for infections. Our goal is to identify targeted immunomodulatory (not, immunosuppressants) with a high benefit-to-risk ratio. We recently identified the commonly prescribed antibiotic, Azithromycin (AZM), as an immunomodulatory agent with neuroprotective effects in spinal cord injury. Because of its safety profile, AZM is frequently prescribed as a prophylactic treatment in several conditions and broadly administered in at-risk disease populations. This proposal aims to provide proof-of- principal data for AZM as a safe and effective neuroinflammatory modulatory drug. We will test the central hypothesis that AZM can alter neuroinflammation and improve cognitive outcomes following a CHI in an APP/PS1 KI mouse model of Alzheimer’s disease-related pathology in the following two specific aims (SA). SA1: Define the immunomodulatory dose-dependent effect of AZM in 8-month-old APP/PS1 KI mouse model following a CHI. SA2: Evaluate the effects of AZM on CHI-induced behavioral and Alzheimer’s disease-related neuropathology in 8-month-old APP/PS1 KI mice. This proof-of-concept study could establish AZM as a safe and well-tolerated FDA-approved drug to reduce damage and speed recovery in the fragile older brain following a CHI. Once the feasibility of AZM treatment has been established, new areas of drug development and clinical research with the potential to more quickly develop a new drug to slow the devastating effects of Alzheimer’s disease can be created.

项目概要/摘要 CDC 估计至少 200,000 名美国老年人（> 65 岁）将遭受创伤性脑损伤 (TBI) 每年，主要是由跌倒造成的闭合性头部损伤（CHI）造成的。大脑老化，患有阿尔茨海默病。神经病理变化，具有显着的反应性小胶质细胞和星形胶质细胞等标志物神经炎症会进一步恶化这种反应性神经胶质增生状态。考虑到病理学因素，阿尔茨海默氏病带来了重大的治疗挑战。然而，我们相信防止病情恶化是一个可以实现的治疗目标。对于那些有患阿尔茨海默病风险的人来说，后天性脑损伤引起的神经炎症。控制老年人 TBI 后的神经炎症是改善患者病情的一个有希望的途径然而，目前还没有药物获得 FDA 批准用于治疗轻度 TBI。指导 FDA 批准的针对神经炎症的药物的重新利用的证据，用于这种独特的治疗不建议使用广谱免疫抑制剂，而应选择选择性生物制剂（例如抗 TNF）很有前途，但它们也存在增加感染的风险，这对于老年人来说是个问题我们的目标是确定有针对性的免疫调节剂（不是，我们最近确定了具有高效益风险比的常用处方。抗生素阿奇霉素（AZM）作为一种免疫调节剂，对脊髓具有神经保护作用由于其安全性，AZM 经常被用作多种疾病的预防性治疗。该提案旨在提供证据- 我们将测试 AZM 作为安全有效的神经炎症调节药物的主要数据。假设 AZM 可以改变神经炎症并改善 CHI 后的认知结果 APP/PS1 KI小鼠模型的阿尔茨海默病相关病理有以下两个具体目标（SA）。 SA1：定义 AZM 对 8 个月大 APP/PS1 KI 小鼠的免疫调节剂量依赖性作用遵循 CHI 的模型。 SA2：评估 AZM 对 CHI 诱发的行为和阿尔茨海默病相关的影响 8 个月大 APP/PS1 KI 小鼠的神经病理学。这项概念验证研究可以将 AZM 确立为 FDA 批准的安全且耐受性良好的药物，以减少一旦 AZM 治疗可行，CHI 后脆弱的老年大脑就会受到损伤并加速恢复。已经建立了新的药物开发和临床研究领域，有可能更快地开发一种新药来减缓阿尔茨海默病的破坏性影响是可能的。