A Proof of Concept Trial of a Sirtuin-NAD+ Activator in Alzheimer's Disease

Sirtuin-NAD 激活剂治疗阿尔茨海默病的概念验证试验

• 批准号: 10457489
• 负责人: SHALENDER BHASIN
• 金额: $ 87.31万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457489
• 关键词: Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Amyloid deposition; Attenuated; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Caloric Restriction; Cerebrospinal Fluid; Chemistry; Clinical; Clinical Pharmacology; Clinical Trials; Coagulation Process; Cognition; Collection; Confidence Intervals; Controlled Study; Data; Deacetylase; Development; Dose; Double-blind trial; Drug Kinetics; Electrocardiogram; Ensure; Enzymes; F2-Isoprostanes; Family; Formulation; Foundations; Geroscience; Glial Fibrillary Acidic Protein; Glycosylated hemoglobin A; Human; IGF1 gene; IL6 gene; Insulin; Investments; Laboratories; Light; Magnetic Resonance Spectroscopy; Measurement; Measures; Mediating; Methodology; Methods; Microglia; Mitochondria; Nerve Degeneration; Niacinamide; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Oral; Oral Administration; Outcome; Participant; Pathway interactions; Penetration; Peptides; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Physiological; Placebo Control; Placebos; Pre-Clinical Model; Procedures; Process; Randomized; Recommendation; Regimen; Regulation; Role; SIRT1 gene; Safety; Serious Adverse Event; Serum; Sirtuins; Site; Structure; TNF gene; Testing; Up-Regulation; abeta toxicity; adverse event monitoring; alpha secretase; amyloid precursor protein processing; circulating biomarkers; cognitive function; crystallinity; design; dietary supplements; efficacy trial; improved; innovation; instrumental activity of daily living; neurofilament; neurogranin; neuroinflammation; neuron regeneration; neuropsychiatric symptom; nicotinamide-beta-riboside; pharmacokinetics and pharmacodynamics; phase 1 study; pre-clinical; prevent; randomized trial; response; sample collection; synaptic function; tau Proteins; tau-1; urinary

Summary In preclinical models, the upregulation of the sirtuin-NAD+ pathway by increasing intracellular NAD+ through administration of NAD precursors, such as β nicotinamide mononucleotide (βNMN), engages the mechanisms of aging and prevents or attenuates Alzheimer's disease (AD) pathology. In contrast to many AD drugs in development that target one mechanism, NAD precursors may prevent AD pathology by multiple mechanisms: by improving mitochondrial energetics; inducing a switch to non-amyloidogenic processing of amyloid precursor protein (APP) due to increased α-secretase activity; preventing microglia-dependent Aβ toxicity; attenuating neuroinflammation; promoting neuronal regeneration; and improving insulin action. NAD- precursors are sold over the counter, and despite widespread claims of their benefits and growing use of NAD precursors, carefully controlled studies of their pharmacology, efficacy, and safety have been limited. In response to the Reviewers' recommendations, we have extensively revised the study and now propose a smaller, single-site, 90-day randomized, placebo-controlled, parallel group, double-blind, trial in 24 participants with mild AD dementia to demonstrate: 1) CNS penetration across the blood-brain barrier; and 2) the ability of oral NMN to increase brain levels of NAD, using an innovative ultra-high field 7T magnetic resonance spectroscopy (MRS) method. To determine whether βNMN penetrates the blood-brain barrier in humans, we will measure the cerebrospinal fluid (CSF) concentrations of βNMN and its key metabolites at baseline and on day 90 (Aim 1). We will assess whether βNMN engages the target mechanism by measuring the abundance of NAD+ (a SIRT1 substrate) in the brain using ultra-high field 7T MRS and in peripheral blood mononuclear cells using a validated LC-MS/MS assay (Aim 2). We will determine the effects of βNMN on circulating biomarkers of aging that the geroscience experts have recommended (HbA1C, IGF1, T3, IL6, TNFα, and urinary F2- isoprostane) (Aim 3). This trial is neither long enough nor large enough to determine the effects of βNMN on clinical outcomes and AD biomarkers. However, we have included CSF and serum biomarkers of AD as well as measures of global cognition, instrumental activities of daily living, and neuropsychiatric symptoms as exploratory outcomes to estimate design parameters such as bias and precision of changes in outcomes, and pre-post correlation to guide the design of subsequent efficacy trials. The scientific rigor and innovation in the proposed proof-of-principle trial is underscored by the use of a high quality crystalline formulation of βNMN; a dose-regimen informed by carefully performed pharmacokinetic studies; rigorous sample collection procedures to ensure preanalytical stability; and evaluating the engagement of the sirtuin-NAD+ pathway in the brain using ultra-high field 7T MRS. The trial will provide important information on the engagement of target mechanisms that is necessary for guiding the stepwise progression of this promising molecule towards larger efficacy trials.

概括 在临床前模型中，通过增加细胞内 NAD+ 来上调 Sirtuin-NAD+ 通路 施用 NAD 前体，例如 β 烟酰胺单核苷酸 (βNMN)，会涉及以下机制 延缓衰老并预防或减轻阿尔茨海默病 (AD) 病理。与许多 AD 药物相比 针对一种机制的开发，NAD 前体可以通过多种机制预防 AD 病理： 通过改善线粒体能量；诱导淀粉样蛋白转为非淀粉样蛋白形成加工 由于 α-分泌酶活性增加，导致前体蛋白 (APP) 增加；预防小胶质细胞依赖性 Aβ 毒性； 减轻神经炎症；促进神经元再生；并改善胰岛素作用。 NAD- 前体在柜台上出售，尽管人们广泛声称其好处并且 NAD 的使用越来越多 前体，对其药理学、功效和安全性的仔细对照研究受到限制。 为了响应评审员的建议，我们对研究进行了广泛的修改，现在提出 规模较小、单中心、为期 90 天的随机、安慰剂对照、平行组、双盲、24 名参与者试验 轻度 AD 痴呆证明：1) CNS 穿透血脑屏障； 2) 的能力 口服 NMN 使用创新的超高场 7T 磁共振来增加大脑中的 NAD 水平 光谱法（MRS）。为了确定 βNMN 是否能穿透人体血脑屏障，我们 将测量基线和治疗后 βNMN 及其关键代谢物的脑脊液 (CSF) 浓度 第 90 天（目标 1）。我们将通过测量 βNMN 的丰度来评估 βNMN 是否参与目标机制。 使用超高场 7T MRS 检测大脑中和外周血单核细胞中的 NAD+（一种 SIRT1 底物） 使用经过验证的 LC-MS/MS 测定（目标 2）。我们将确定 βNMN 对循环生物标志物的影响 老年科学专家推荐的衰老指标（HbA1C、IGF1、T3、IL6、TNFα 和尿 F2- 异前列烷）（目标 3）。该试验的时间和规模都不足以确定 βNMN 对 临床结果和 AD 生物标志物。然而，我们也包括了 AD 的脑脊液和血清生物标志物 作为整体认知、日常生活的工具性活动和神经精神症状的衡量标准 探索性结果来估计设计参数，例如结果变化的偏差和精度，以及 前后相关性以指导后续疗效试验的设计。 所提出的原理验证试验的科学严谨性和创新性通过使用高 βNMN的优质结晶配方；根据仔细执行的药代动力学确定的剂量方案 研究；严格的样品采集程序，确保分析前的稳定性；并评估参与度 使用超高场 7T MRS 观察大脑中的 Sirtuin-NAD+ 通路。该试验将提供重要的 有关目标机制参与的信息，这些信息对于指导逐步进展是必要的 这种有前途的分子有望进行更大规模的功效试验。