Safety and modulation of ABCC9 pathways by nicorandil for the treatment of hippocampal sclerosis of aging

尼可地尔治疗老年海马硬化的安全性和对 ABCC9 通路的调节

• 批准号: 9850912
• 负责人: GREGORY A JICHA
• 金额: $ 74.09万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9850912
• 关键词: 3-Dimensional; ABCC9 gene; Affect; Age; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Autopsy; Biological Assay; Biological Markers; Brain; CRSP3 gene; Cardiovascular system; Clinical; Clinical Trials; Cognition; Complement; Congestive Heart Failure; Data; Degenerative Disorder; Dementia; Diagnosis; Differential Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Double-Blind Method; Drug usage; Elderly; Future; Genes; Heart failure; Hippocampus (Brain); Human; Impaired cognition; Individual; Kentucky; Life; Link; Longitudinal cohort; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Metabolic; Morbidity - disease rate; Nerve Degeneration; Neurocognitive; Neurofibrillary Tangles; Nicorandil; Outcome Measure; Participant; Pathology; Pathway interactions; Persons; Pharmacology; Pharmacotherapy; Phase; Placebos; Population; Prevention trial; Prospective cohort; Proteins; Proteomics; Publishing; Randomized; Research; Risk; Running; Safety; Spin Labels; Structure; Techniques; Testing; Universities; Urea; Work; aging population; base; cognitive testing; cohort; cost; design; disease diagnosis; drug discovery; drug repurposing; early phase clinical trial; efficacy outcomes; genetic risk factor; high risk; hippocampal atrophy; hippocampal sclerosis; magnetic resonance imaging biomarker; neurocognitive test; neuroimaging; neuropathology; novel; novel therapeutics; prevent; primary endpoint; primary outcome; randomized placebo-controlled clinical trial; receptor; safety testing; sex; tau Proteins; tau-1; treatment duration; trial design; volunteer

Abstract The proposed project is a pilot clinical trial investigating a potential treatment for hippocampal sclerosis of aging (HS-Aging). A major subtype of “Alzheimer's disease and related dementia” (ADRD), HS-Aging affects 10-25% of all elderly individuals. HS-Aging is typically misdiagnosed as Probable AD or AD-type dementia in the clinical setting. Unfortunately, there currently is no validated biomarker to diagnose HS-Aging during life, and there is no known therapy. We will test the safety and efficacy of nicorandil for HS-Aging, based on our prior work elucidating a pharmacologically targetable mechanism underlying the disease. Nicorandil is a vasorelaxant drug, used clinically to treat chronic heart failure in the elderly population. Pharmacologically, Nicorandil is an agonist for a protein (SUR2) that is encoded by a gene that we found to be linked to HS-Aging risk. Primary specific aims follow: Specific Aim #1: Evaluate safety and neurodegenerative biomarkers linked to HS-Aging pathology in nicorandil vs. placebo treated subjects by: a. Conducting a double-blind, randomized, placebo-controlled, clinical trial of nicorandil in 62 participants (both sexes, >75 years old, CDR 0.5 or 1, with HS-Aging profile in CSF and MRI biomarkers [amyloid and phospho-tau negative, with evidence for hippocampal atrophy; A-/T-/N+]) over a 96-week treatment period; b. Evaluating the safety of nicorandil administration in the elderly at risk for HS-aging (this is the primary outcome measure) that will inform future trial design; and, c. Measuring structural MRI (3D-T1; hippocampal atrophy is the main efficacy outcome measure), cognitive tests, and CSF levels of nicorandil, tau, phospho-tau, and Aβ(1-42) at baseline and week 96. Specific Aim #2: Optimize and further explore HS-Aging biomarkers by: a. Refining MR imaging analysis (including hippocampal volumetric assays, arterial spin labeling (ASL), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS) techniques that may distinguish participants with probable HS-Aging from those with positive AD biomarkers; b. Performing proteomic discovery analysis in CSF to identify and evaluate potential HS-Aging biomarkers to complement the A/T/N framework utilizing our prospective cohort with Aβ(1-42), phospho-tau, and neurodegeneration markers and MR imaging as a control cohort for AD. This specific aim will directly test and enhance the clinical utility of the A/T/N framework for diagnosis of degenerative disease state; and, c. Following our published and replicated neurocognitive testing marker that is associated with HS-Aging pathology, we will optimize the clinical and neurocognitive criteria for disease diagnosis based on the prospects of a relatively long-running (96 week) early-phase clinical trial.

抽象的 拟议的项目是一项试点临床试验，调查海马的潜在治疗方法 老化硬化（HS-Aging）。 “阿尔茨海默病和相关痴呆”（ADRD）的一个主要亚型， HS-Aging 影响 10-25% 的老年人。 HS-Aging 通常被误诊为可能的 AD 或临床上的 AD 型痴呆。不幸的是，目前还没有经过验证的生物标志物 在一生中诊断 HS-Aging，并且没有已知的治疗方法。 我们将根据我们之前阐明的工作，测试尼可地尔用于 HS-Aging 的安全性和有效性 疾病背后的药理学靶向机制。尼可地尔是一种血管舒张药， 临床上用于治疗老年人慢性心力衰竭。尼可地尔的药理作用是 一种蛋白质 (SUR2) 的激动剂，该蛋白质由我们发现与 HS 老化风险相关的基因编码。 主要具体目标如下： 具体目标#1：评估与 HS-Aging 相关的安全性和神经退行性生物标志物 尼可地尔与安慰剂治疗受试者的病理学表现如下： 一个。对 62 名患者进行尼可地尔的双盲、随机、安慰剂对照临床试验 参与者（男女，>75 岁，CDR 0.5 或 1，脑脊液和 MRI 中具有 HS-Aging 特征） 生物标志物[淀粉样蛋白和磷酸tau蛋白阴性，有海马萎缩的证据； A-/T-/N+]) 超过 96 周的治疗期； b.评估老年人服用尼可地尔的安全性 HS 老化风险（这是主要结果指标）将为未来的试验设计提供信息；以及，c。 测量结构 MRI（3D-T1；海马萎缩是主要疗效结果测量）， 基线和第 96 周的认知测试以及脑脊液中尼可地尔、tau、磷酸-tau 和 Aβ(1-42) 的水平。 具体目标 #2：通过以下方式优化并进一步探索 HS-Aging 生物标志物： 一个。完善 MR 成像分析（包括海马体积测定、动脉自旋标记 (ASL)、扩散张量成像 (DTI)、磁共振波谱 (MRS) 技术 将可能患有 HS-Aging 的参与者与 AD 生物标志物呈阳性的参与者区分开来； b.表演 CSF 中的蛋白质组学发现分析，用于识别和评估潜在的 HS-Aging 生物标志物 利用我们的前瞻性队列补充 A/T/N 框架，包括 Aβ(1-42)、磷酸化 tau 和 神经变性标记物和 MR 成像作为 AD 的对照队列。这一具体目标将直接 测试并增强 A/T/N 框架诊断退行性疾病状态的临床实用性； 以及，c。遵循我们发布和复制的与以下相关的神经认知测试标记 HS-衰老病理学，我们将优化疾病诊断的临床和神经认知标准 基于相对长期（96 周）的早期临床试验的前景。