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，其临床特征如 记忆丧失认知障碍和痴呆AD影响超过500万美国人，是第六大 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。鉴于持续的 由于AD药物在临床试验中的失败和争议，确定新的靶点以开发有效的药物是至关重要的。 治疗AD。 文献支持的一种新的潜在治疗方法是纠正异常的神经胶质细胞， 激活和神经炎症，导致神经元变性和AD进展。Pelagos Pharma 目的是通过靶向核受体和转录抑制因子REV-ERB β， Pelagos的共同创始人和核受体专家托马斯伯里斯对新靶点进行了广泛的研究， PhD. REV-ERB在大脑中高度表达，并作为转录抑制因子发挥作用， 调节小胶质细胞中多种炎性成分的表达，特别是NLRP 3炎性体 和促炎细胞因子如IL-6、IL-1 β和IL-18。在多种体外和体内AD模型中，REV- 工具化合物的ERB激动作用减少神经炎症并防止记忆丧失。 Pelagos现在正在开发第一种临床上可行的小分子激动剂，靶向REV-ERB受体， 抑制神经炎症和治疗AD。靶向REV-ERB抑制剂通过抑制 NLRP 3炎性体表达和随后的形成是一种创新方法，具有巨大的生物学意义。 有可能减轻症状并有效减轻AD相关负担。我们的方法是独一无二的- 竞争对手针对个别炎性小体成分，这种方法可能会导致公正的 抑制，有限的功效和增加的潜在负面反弹效应。通过瞄准上游 调节小胶质细胞中炎性小体和细胞因子的表达，我们可以将炎性小体和细胞因子的表达 这些成分可以降低到基础水平，并在很长一段时间内限制慢性炎症。 第一阶段SBIR的目标是从我们的衍生化合物短名单中选择一个主要候选物。 专利支架（目标1），并在多个体外和体内试验中建立安全性和有效性概念验证 神经炎症和AD模型（目的2）。我们将采取系统的成本效益和时间效益的方法， 基于DMPK性质和在良好建立的模型中的功效结果选择最佳化合物， 从筛选多种化合物的高通量测定开始， 模型来评估最佳化合物1。该第一阶段提案的产品将是一种口服生物可利用的小分子药物， 分子REV-ERB β激动剂，具有有利的PK/PD，可以穿过血脑屏障， AD模型中的神经炎症。第一阶段的成功完成将使Pelagos能够提高 完成长期安全性和有效性试验并启动IND启动研究所需的资金。