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+通过 施用NAD前体，例如β烟酰胺单核苷酸（βNMN） 衰老和阻止或减弱阿尔茨海默氏病（AD）病理学。与许多AD药物相反 针对一种机制的开发，NAD前体可能会通过多种机制来防止AD病理： 通过改善线粒体能量学；诱导转向淀粉样蛋白的非淀粉样蛋白生成加工 由于α-分泌酶活性的增加，前体蛋白（APP）；防止小胶质细胞依赖性Aβ毒性； 衰减神经炎症；促进神经元再生；并改善胰岛素作用。 nad- 前体是在柜台上出售的，dospite的宽度主张其利益和日益增长的NAD使用 前体，对其药理学，有效性和安全性的精心控制的研究受到限制。 为了回应审稿人的建议，我们对研究进行了广泛的修订，现在提出了 较小的，单位的，90天随机，安慰剂对照，平行组，双盲，24个参与者试验 用轻度的AD痴呆症证明：1）CNS穿透在血脑屏障中； 2） 使用创新的超高场7T磁共振，口服NMN增加了NAD的大脑水平 光谱法（MRS）方法。为了确定βNMN是否穿透了人类的血脑屏障，我们 将测量βNMN的脑脊液（CSF）浓度及其在基线时的关键代谢产物 第90天（目标1）。我们将通过测量抽象来评估βNMN是否参与目标机制 使用超高场7T MRS和外周血单核细胞中的NAD+（SIRT1底物）在大脑中 使用经过验证的LC-MS/MS分析（AIM 2）。我们将确定βNMN对循环生物标志物的影响 衰老已经推荐了GEROSCIENCE专家（HBA1C，IGF1，T3，IL6，TNFα和尿F2- 异丙烷）（目标3）。该试验既不足够长，也不够大，无法确定βNMN的影响 临床结果和广告生物标志物。但是，我们还包括CSF和AD的血清生物标志物 作为全球认知，日常生活的工具活动和神经精神症状的衡量标准 探索性结果以估计设计参数，例如偏见和结果的变化精度，以及 指导后续有效性试验设计的前相关性。 拟议原理验证试验中的科学严谨和创新是通过使用高 βNMN的质量结晶式；通过精心执行的药代动力学告知的剂量尺度 研究；严格的样品收集程序，以确保放分析稳定性；并评估参与 使用超高场7T MRS，大脑中的Sirtuin-NAD+途径试验将提供重要的 有关引导逐步发展目标机制参与目标机制的信息 这有望进行更大的效率试验。