(-)-Phenserine inhibition of neuronal death in Alzheimer’s disease and developing brain-labeled plasma exosomes assays as biomarkers for a phenserine phase 1b ascending dose trial

(-)-Phenserine 抑制阿尔茨海默病中的神经元死亡，并开发脑标记血浆外泌体检测作为 phenserine 1b 期剂量递增试验的生物标志物

• 批准号: 10365975
• 负责人: Clive Ballard
• 金额: $ 68.48万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10365975
• 关键词: Address; Adverse event; Affect; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; American; Anatomy; Animals; Anoxia; Apoptosis; Astrocytes; Autophagocytosis; BAX gene; BCL2 gene; Biochemical; Biological Assay; Biological Markers; Brain; CASP3 gene; Cell Death; Cell physiology; Cells; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Cohort Studies; Collaborations; Companions; Dementia; Development; Diagnosis; Disease; Disease Marker; Dose; Drug Kinetics; Drug Monitoring; Evaluation; Formulation; Foundations; Functional disorder; Future; Genes; Goals; Human; Impaired cognition; Impairment; Inflammation; Inflammatory; Intervention; Label; Legal patent; Maintenance; Maximum Tolerated Dose; Measures; Modeling; Modification; Molecular; Nerve Degeneration; Neuronal Dysfunction; Neuronal Injury; Neurons; Older Population; Oral; Outcome; Participant; Pathology; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Placebo Control; Placebos; Plasma; Pre-Clinical Model; Preparation; Prevention; Process; Process Measure; Proteins; Randomized; Rattus; Reproducibility; Research Personnel; Role; Safety; Sampling; Source; Synapses; Synapsins; Synaptophysin; TP53 gene; Tablets; Tartrates; Testing; Therapeutic; Time; Translational Research; Translations; Traumatic Brain Injury; Wild Type Mouse; base; biological development; clinical development; clinically relevant; clinically translatable; cohort; controlled release; cytokine; drug development; effective therapy; efficacy evaluation; exosome; improved; inhibitor; interest; multidisciplinary; neurogranin; neuroinflammation; neuron loss; neuropathology; novel; phenserine; pre-clinical; predicting response; preservation; prevent; protein expression; response; response biomarker; sound; synaptopodin; synaptotagmin II; tablet formulation; tool; transgenic model of alzheimer disease

There are no effective drugs to prevent, delay or treat Alzheimer’s disease (AD). The 5 million Americans currently diagnosed with AD is projected to increase to 11-16 million within two decades in the absence of effective therapies. We propose to develop for use in humans, plasma based exosome biomarker assays specifically reflecting the real-time biochemical state present in brain neurons and astrocytes. This advance will allow investigators real time assessments of AD neuropathology and opportunities to monitor drug effects. (-)-Phenserine tartrate is both a proven probe able to affect AD neuropathology that is considered important in progression to dementia, and a potential therapeutic operating independently from the AD pathology targeted over the last 30 years. Anatomical and biochemical evidence from preclinical transgenic AD models and wild type mice and rats in traumatic brain injury (TBI) and anoxia models support the translation of phenserine protection of neurons from preprogrammed cell death (PPCD) unexplained by other activities of phenserine. We have developed an extended controlled release formulation of phenserine tartrate to insure successful determination of optimal dosing that maximizes preservation of neurons and expected prevention of dementia. Based on a foundation of preclinical discovery, translational research (TBI and AD trials), clinical development at NIA, and FDA assessment, we propose a phase 1b ascending dose clinical trial of four phenserine doses given daily for 12 weeks to establish a safe and tolerated dose, to characterize biomarker responses, and to interpret their significance for cellular functioning. This dose-response evaluation prepares for advancement to a phase 2 proof of concept trial. Two specific aims are proposed to achieve this goal: Aim 1 to assess the performance of the exosome biomarkers, their ability to distinguish AD pathology from not impaired, their reproducibility, and precision in older populations; Aim 2 to conduct a phase 1b ascending dose trial of phenserine in early AD. Primary safety objectives are to define a maximally tolerated dose, and determine treatment emergent adverse events. Biomarker objectives are to enable the deployment of exosomes assays as measures of AD neuropathology and phenserine’s effects on pathology. Secondary objectives are to: 1) assess potential short-term effects of phenserine on cognition; 2) inform an ensuing phase 2 proof of concept trial with exosome biomarkers, i.e., PPCD, synaptic arborization, etc. A multi- disciplinary investigator team with expertise in drug development, biomarkers of cognitive impairment, aging, and translational research for Alzheimer therapeutics is committed to the project. Outcomes will provide: 1) an estimated safe, well-tolerated phenserine dose; 2) parameter estimates for the exosome biomarkers; and 3) parameter estimates for cognitive efficacy to advance to phase 2. The proposal meets objectives of NIA PAR- 18-175, Pilot Clinical Trials for the Spectrum of Alzheimer's Disease and Age-related Cognitive Decline.

目前还没有有效的药物来预防、延缓或治疗阿尔茨海默病（AD）。五百万美国人