Anti-Viral therapy in Alzheimer's disease

阿尔茨海默病的抗病毒治疗

• 批准号: 9442894
• 负责人: DAVANGERE P DEVANAND
• 金额: $ 132.78万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9442894
• 关键词: Acyclovir; Address; Adult; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid beta-Protein; Anterior; Antibodies; Antibody titer measurement; Antiviral Agents; Apolipoprotein E; Axonal Transport; Biological Assay; Biological Markers; Brain; Brain Diseases; Cells; Cessation of life; Chronic; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; DNA; DNA-Directed DNA Polymerase; Dementia; Disease; Disease Progression; Dose; Double-Blind Method; Drops; Etiology; Funding; Generic Drugs; Genotype; Herpesviridae; Herpesvirus 1; Human; Human Herpesvirus 2; Human Herpesvirus 4; Human Herpesvirus 8; Immune; Immunoglobulin G; Immunoglobulin M; Impaired cognition; Infection; Infectious Agent; L Cells; Latent Virus; Lead; Lesion; Magnetic Resonance Imaging; Measures; Medial; Memory; Memory B-Lymphocyte; MicroRNAs; Microbe; Multiple Sclerosis; Muridae; Mus; Myeloid Cells; Nerve; Nerve Degeneration; Neurons; Olfactory Receptor Neurons; Oral; Outcome; Outcome Measure; Parietal; Pathology; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phosphorylation; Placebo Control; Placebos; Plasma; Play; Positron-Emission Tomography; Prodrugs; Protein-Serine-Threonine Kinases; Randomized; Recurrence; Research Design; Role; Scanning; Schizophrenia; Senile Plaques; Senior Scientist; Serum; Simplexvirus; Spinal Puncture; Stress; Structure of trigeminal ganglion; Sum; Temporal Lobe; Testing; Thinness; Thymidine Kinase; Viral; Viral Antibodies; Virus; Virus Latency; cognitive testing; editorial; genital herpes; high reward; innovation; macromolecule; multiple sclerosis patient; oral infection; particle; phase 3 study; phase II trial; reactivated HSV-1; seropositive; slow potential; tau Proteins; tau aggregation; treatment trial; tripolyphosphate; uptake; valacyclovir; week trial

Many viruses are latent for decades before being reactivated in the brain by stress, immune compromise, or other factors. After the initial oral infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and can later enter the brain via retrograde axonal transport, often targeting the temporal lobes. HSV1 can also enter the brain via olfactory neurons directly. HSV1 (oral herpes) and HSV2 (genital herpes) are known to trigger amyloid aggregation and their DNA is commonly found in amyloid plaques. Anti-HSV drugs reduce Aβ and p-tau accumulation in brains of infected mice. HSV1 reactivation is associated with tau hyperphosphorylation in mice and may play a role in tau propagation across neurons. In humans, recurrent reactivation with newly produced HSV1 particles, 'drop by drop,' may produce neuronal damage and eventually lead to neurodegeneration and Alzheimer's disease (AD) pathology, partly due to effects on amyloid and tau. Clinical studies show cognitive impairment in HSV seropositive patients in different patient groups and in healthy adults, and antiviral treatments show robust efficacy against peripheral HSV infection. We will conduct the first-ever clinical trial to directly address the long-standing viral etiology hypothesis of AD which posits that viruses, particularly the very common HSV1 and HSV2, may be etiologic or contribute to the pathology of AD. In patients with mild AD who test positive for serum antibodies to HSV1 or HSV2, the generic antiviral drug valacyclovir, repurposed as an anti-AD drug, will be compared at oral doses of 2 to 4 g per day to matching placebo in the treatment of 130 patients (65 valacyclovir, 65 placebo) in a randomized, double-blind, 78-week Phase II proof of concept trial. Patients treated with valacyclovir are hypothesized to show smaller decline in cognition and functioning compared to placebo, and, using 18F-Florbetapir PET imaging, to show less amyloid accumulation than placebo over the 78-week trial. Apolipoprotein E genotype at baseline, as well as changes in cortical thinning on structural MRI, olfactory identification deficits, and antiviral antibody titers from baseline to 78 weeks, will be evaluated in exploratory analyses. In patients who agree to lumbar puncture, plasma and CSF acyclovir will be assayed to establish the degree of CNS penetration of valacyclovir in mild AD, and we will obtain CSF Aβ42, tau, p-tau for subset exploratory analyses with changes in outcome measures. If this trial is successful, we will apply for funding to conduct a larger, multicenter, Phase III study using a study design that will be informed by the results of this Phase II trial. This innovative Phase II proof of concept trial clearly has exceptionally high reward potential for the treatment of AD.

许多病毒潜伏数十年，然后在大脑中因压力、免疫妥协或 其他因素。在最初的口腔感染后，单纯疱疹病毒-1(HSV1)在三叉神经处潜伏 神经节，随后可通过逆行轴突运输进入大脑，通常以颞叶为靶点。 HSV1也可以通过嗅觉神经元直接进入大脑。HSV1(口腔疱疹)和HSV2(生殖器疱疹) 已知会引发淀粉样蛋白聚集，它们的DNA通常存在于淀粉样斑块中。抗单纯疱疹病毒 药物可减少A-β和p-tau在感染小鼠脑内的蓄积。HSV1重新激活与tau相关 在小鼠中过度磷酸化，并可能在tau跨神经元传播中发挥作用。在人类中，复发性 重新激活新产生的HSV1颗粒，一滴一滴地，可能会导致神经元损伤，并最终 导致神经变性和阿尔茨海默病(AD)的病理，部分是由于对淀粉样蛋白和tau的影响。 临床研究表明，HSV血清阳性患者在不同的病例组中存在认知障碍 健康成人和抗病毒治疗对外周HSV感染显示出强大的疗效。我们将进行 首次直接解决长期存在的AD病毒病因学假说的临床试验 病毒，特别是非常常见的HSV1和HSV2，可能是AD的病因或参与了AD的病理。 在血清HSV1或HSV2抗体检测呈阳性的轻度AD患者中，非专利抗病毒药物HSV1或HSV2 万乃洛韦被重新用作抗阿尔茨海默病的药物，将以每天2-4g的口服剂量进行比较，以匹配 安慰剂治疗130例患者(万乃洛韦65例，安慰剂65例)随机、双盲、78周 第二阶段概念证明审判。接受万乃洛韦治疗的患者被假设显示出较小的下降 认知和功能与安慰剂相比，并使用18F-Florbetapir PET成像显示较少的淀粉样蛋白 在78周的试验中积累的药物多于安慰剂。载脂蛋白E在基线水平的基因分型及其变化 结构MRI上皮质变薄、嗅觉识别缺陷和抗病毒抗体滴度从基线开始 至78周，将在探索性分析中进行评估。对于同意腰椎穿刺术的患者，血浆和 将测定脑脊液中阿昔洛韦的浓度，以确定万乃洛韦在轻度AD中的中枢神经系统渗透程度。 将获得脑脊液Aβ42，tau，p-tau，用于带有结果指标变化的子集探索性分析。如果这场审判 如果成功，我们将申请资金，使用研究设计进行更大的、多中心的第三阶段研究 这将从第二阶段试验的结果中得知。这一创新的第二阶段概念验证试验清楚地 对阿尔茨海默病的治疗具有极高的回报潜力。