Anti-Viral therapy in Alzheimer's disease

阿尔茨海默病的抗病毒治疗

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

许多病毒在通过压力，免疫妥协或其他因素。初始口腔感染后，单纯疱疹病毒1（HSV1）在三叉神经中变得潜在神经节，随后可以通过逆行轴突运输进入大脑，通常针对临时爱。 HSV1也可以直接通过嗅觉神经元进入大脑。 HSV1（口腔疱疹）和HSV2（生殖器疱疹）已知会触发淀粉样蛋白聚集，其DNA通常在淀粉样斑块中发现。抗HSV 药物减少了感染小鼠的大脑中的Aβ和P-TAU积累。 HSV1重新激活与Tau有关小鼠的高磷酸化，可能在神经元之间的tau传播中发挥作用。在人类中，经常性用新生产的HSV1颗粒重新激活，“滴下降”可能会产生神经元损害，最终会产生导致神经变性和阿尔茨海默氏病（AD）病理学，部分原因是对淀粉样蛋白和TAU的影响。临床研究表明，不同患者组的HSV血清阳性患者以及健康的成年人和抗病毒治疗对外周HSV感染显示出强大的效率。我们将进行有史以来第一个直接解决了AD的长期病毒病因假说的临床试验，该假设认为病毒，特别是非常常见的HSV1和HSV2，可能是病因或有助于AD的病理学。在对HSV1或HSV2的血清抗体测试阳性的轻度AD患者中，通用抗病毒药物 Valacyclovir（将其重新替换为抗AD药物）将以每天2至4 g的口服剂量进行比较以匹配安慰剂在130名患者（65例Valacyclovir，65个安慰剂）治疗中第二阶段概念验证试验。假设接受Valacyclovir治疗的患者显示出较小的下降与安慰剂相比，认知和功能，并使用18F氯贝氏宠物成像显示较少的淀粉样蛋白在为期78周的试验中，积累比安慰剂。基线时载脂蛋白E基因型以及变化在结构MRI上的皮质稀疏中，嗅觉鉴定缺陷和基线的抗病毒抗体到78周，将在探索性分析中进行评估。在同意腰穿，等离子体和的患者中 CSF Acyclovir将被分配以建立Valacyclovir在轻度AD中的中枢神经系统渗透程度，而我们将获得CSFAβ42，TAU，P-TAU进行子集探索性分析，并随着结果度量的变化。如果此试验成功，我们将申请使用研究设计的资金进行更大的多中心，第三阶段的研究这将由本II阶段试验的结果告知。这种创新的II阶段概念验证验证清楚对AD的治疗具有极高的奖励潜力。