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.

摘要 在临床前模型中，sirtuin-NAD+途径通过增加细胞内NAD+而上调 NAD前体的给药，如β烟酰胺单核苷酸(βNMN)，参与了这种机制 抗衰老，预防或减轻阿尔茨海默病(AD)的病理。与许多AD药物相比， 针对一种机制的发展，NAD前体可能通过多种机制预防AD病理： 通过改善线粒体能量学；诱导向淀粉样蛋白的非淀粉样变性过程转变 由于α分泌酶活性增加而产生的前体蛋白(APP)；防止小胶质细胞依赖的Aβ毒性； 减轻神经炎症；促进神经元再生；改善胰岛素作用。NAD- 前体是在柜台上销售的，尽管人们普遍声称它们的好处和NAD的使用越来越多 前体，对其药理、疗效和安全性的仔细对照研究一直受到限制。 因应评审员的建议，我们已对研究作出广泛修订，现建议 规模较小、单部位、90天随机、安慰剂对照、平行分组、双盲、24名参与者的试验 轻度阿尔茨海默病患者表现为：1)中枢神经系统穿过血脑屏障；2) 口服NMN提高大脑NAD水平，使用创新的超高场7T磁共振 光谱学(MRS)方法。为了确定βnmn是否能穿透人类的血脑屏障，我们 将在基线和其他时间测量脑脊液中βNMN及其主要代谢物的浓度 第90天(目标1)。我们将通过测量βNMN的丰度来评估NMN是否参与了靶机制 超高场7T MRS检测脑内NAD+(SIRT1底物)和外周血单核细胞中的NAD+ 使用经过验证的LC-MS/MS分析(目标2)。我们将确定βNMN对循环生物标记物的影响 老年学专家推荐的衰老(糖化血红蛋白、胰岛素样生长因子1、T_3、白介素6、肿瘤坏死因子α和尿F2- 异前列腺素)(目标3)。这项试验既不够长，也不够大，无法确定βNMN对 临床结果和AD生物标志物。然而，我们也包括了脑脊液和AD的血清生物标记物 作为全球认知、日常生活工具活动和神经精神症状的衡量标准，如 用于估计设计参数的探索性结果，例如结果变化的偏差和精确度 前后对照，指导后续疗效试验设计。 拟议的原则证明试验中的科学严谨性和创新性通过使用高 β纳米粒的高质量晶体制剂；通过仔细进行药代动力学了解的剂量方案 研究；严格的样品收集程序，以确保分析前的稳定性；以及评估项目 利用超高场7TMRS对大脑中sirtuin-NAD+通路的研究这项试验将提供重要的 关于指导循序渐进所需的目标机制的信息 这一前景看好的分子将用于更大规模的疗效试验。