Developing Novel REV-ERB Agonists for the Treatment of Neuroinflammation in Alzheimer's Disease

开发用于治疗阿尔茨海默病神经炎症的新型 REV-ERB 激动剂

• 批准号: 10482583
• 负责人: Robert Williams
• 金额: $ 44.95万
• 依托单位: PELAGOS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482583
• 关键词: Address; Adverse effects; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; American; Animal Model; Astrocytes; Award; Biochemical; Biological Assay; Blood - brain barrier anatomy; Brain; CCL2 gene; Capital; Cause of Death; Cells; Cessation of life; Chemicals; Chronic; Circadian Dysregulation; Circadian Rhythms; Clinic; Clinical; Clinical Trials; Cognition; Cognitive deficits; Collaborations; Defect; Dementia; Deposition; Disease Progression; Doctor of Philosophy; Dose; Failure; Funding; Gene Expression; Goals; Hippocampus (Brain); IL18 gene; IL1B gene; Impaired cognition; In Vitro; Individual; Infiltration; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Interleukin-1; Interleukin-18; Interleukin-6; Lead; Literature; Measures; Mediating; Medical; Memory Loss; Microglia; Modeling; Monitor; Morbidity - disease rate; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Nuclear Receptors; Oral; Pharmaceutical Preparations; Pharmacology; Phase; Play; Positioning Attribute; Property; Public Health; Research; Research Priority; Rodent Model; Role; Safety; Senile Plaques; Series; Signal Transduction; Small Business Innovation Research Grant; Source; Therapeutic; Time; Toxic effect; Transcription Repressor; Transgenic Animals; Transgenic Model; United States National Institutes of Health; aging population; base; blood-brain barrier penetration; circadian; clinical candidate; cohort; cost; cost effective; cytokine; design; effective therapy; familial Alzheimer disease; glial activation; high throughput screening; improved; in vitro Model; in vivo; innovation; lead candidate; mortality; neuroinflammation; novel; pharmacokinetics and pharmacodynamics; primary endpoint; reduce symptoms; scaffold; screening; side effect; small molecule; tool; transgenic model of alzheimer disease

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease with clinical hallmarks such as memory loss, cognitive impairment, and dementia. AD affects over 5 million American and is the 6th leading cause of death; these numbers will rise dramatically as the US aging population increases. Given the continued failures and controversies of AD drugs in clinical trials, it is critical to identify novel targets to develop effective therapies for AD. One novel potential therapeutic approach that is supported by the literature is to correct the aberrant glial activation and neuroinflammation that contribute to neuronal degeneration and AD progression. Pelagos Pharma aims to reduce neuroinflammation by targeting the nuclear receptor and transcriptional repressor REV-ERB, a novel target has been extensively studied by Pelagos co-founder and nuclear receptor expert Thomas Burris, PhD. REV-ERB is highly expressed in the brain and functions as a transcriptional repressor to negatively regulate expression of multiple inflammatory components in microglia, particularly the NLRP3 inflammasome and pro-inflammatory cytokines such as IL-6, IL-1, and IL-18. In multiple in vitro and in vivo AD models, REV- ERB agonism with tool compounds reduces neuroinflammation and protects against memory loss. Pelagos is now developing the first clinically-viable small molecule agonists that target REV-ERB to suppress neuroinflammation and treat AD. Targeting REV-ERB to suppress neuroinflammation by inhibiting NLRP3 inflammasome expression and subsequent formation is an innovative approach that has tremendous potential to reduce symptoms and effectively reduce the burdens associated with AD. Our approach is unique - competitors are targeting individual inflammasome components, an approach that may result in impartial suppression, limited efficacy, and increased potential for negative rebound effects. By targeting the upstream regulator of inflammasome and cytokine expression in microglia, we may return expression of inflammatory components to a basal level and limit chronic inflammation for a prolonged period. The goal of this Phase I SBIR is to select a lead candidate from a shortlist of compounds derived from our proprietary scaffold (Aim 1) and establish safety and efficacy proof-of-concept in multiple in vitro and in vivo neuroinflammation and AD models (Aim 2). We will take a systematic cost- and time-effective approach to selecting the optimal compound based on DMPK properties and efficacy results in well-established models, starting with high-throughput assays to screen multiple compounds and ending with long-term transgenic animal models to assess the best 1 compound. The product of this Phase I proposal will be an orally bioavailable small molecule REV-ERB agonist with favorable PK/PD that can cross the blood brain barrier to reduce neuroinflammation in AD models. Successful completion of this phase I will position Pelagos to raise the necessary capital to complete long-term safety and efficacy assays and initiate IND-enabling studies.

阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，具有临床标志，例如 记忆力丧失，认知障碍和痴呆症。广告影响超过500万美国，是第六名 死亡原因；随着美国老龄化人口的增加，这些数字将急剧上升。考虑到继续 在临床试验中，AD药物的失败和争议，确定新的目标以发展有效，这一点至关重要 广告疗法。 文献支持的一种新颖的潜在疗法方法是纠正异常神经胶质 有助于神经元变性和AD进展的激活和神经炎症。 Pelagos Pharma 旨在通过靶向核接收器和转录复制Rev-erb来减少神经炎症 佩拉戈斯联合创始人和核接收器专家托马斯·伯里斯（Thomas Burris）广泛研究了新型目标， 博士学位。 Rev-erb在大脑中高度表达，并作为否定的转录代表发挥作用 调节小胶质细胞中多种炎症成分的表达，特别是NLRP3炎性体 以及促炎性细胞因子，例如IL-6，IL-1和IL-18。在多个体外和体内AD模型中，Rev- 用工具化合物的ERB激动剂减少了神经炎症并防止记忆丧失。 Pelagos现在正在开发第一个临床上可行的小分子激动剂，将Rev-erb靶向 抑制神经炎症并治疗AD。针对Rev-erb通过抑制抑制神经炎症 NLRP3炎性体表达和随后的形成是一种具有巨大的创新方法 减轻症状并有效减少与AD相关的伯良的潜力。我们的方法是独一无二的 - 竞争对手正在针对单个炎性组组件，这种方法可能会导致公正 抑制，有限的有效性以及增加反弹效应的潜力。通过针对上游 小胶质细胞中炎性体和细胞因子表达的调节剂，我们可能会返回炎症的表达 成分达到基本水平，并限制长时间的慢性炎症。 I阶段I SBIR的目标是从我们的化合物入围名单中选择一个铅候选者 专有脚手架（AIM 1）并在多个体外和体内建立安全性和有效性证明 神经炎症和AD模型（AIM 2）。我们将采用系统的成本和时间效率的方法 基于DMPK属性和效率选择最佳化合物会导致建立良好的模型， 从筛选多种化合物的高通量测定开始，然后以长期转基因动物结束 评估最佳1化合物的模型。该阶段I提案的产品将是一个口头的生物利用 具有有利的PK/PD的分子Rev-erb激动剂，可以越过血脑屏障以减少 AD模型中的神经炎症。成功完成此阶段，我将定位Pelagos以提高 完成长期安全性和有效测定并启动辅助研究的必要资本。