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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：
10189468
负责人：
DAVANGERE P DEVANAND
金额：
$ 233.57万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189468
关键词：
Acyclovir Address Adult Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer’s disease biomarker Amino Acids Amyloid Amyloid beta-42 Amyloid beta-Protein Anterior Antibodies Antibody titer measurement Antiviral Agents Antiviral Therapy Apolipoprotein E Axonal Transport Biological Assay Brain 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 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 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 Patients Penetration Peripheral Pharmaceutical Preparations Phase Phosphorylation 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 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 tau-1 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.

许多病毒潜伏了几十年，然后在大脑中因压力、免疫系统受损或其他原因被重新激活