Development of Nav1.1 Enhancers to Treat Alzheimer's Disease

开发 Nav1.1 增强剂来治疗阿尔茨海默病

• 批准号: 10654943
• 负责人: Michael Pleiss
• 金额: $ 124.95万
• 依托单位: CURE NETWORK DOLBY ACCELERATION PARTNERS LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10654943
• 关键词: APP-PS1; Acceleration; Acute; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Animal Model; Astrocytes; Bacterial Artificial Chromosomes; Behavioral; Biological Assay; Biological Availability; Brain; Cardiac; Cell Line; Cells; Central Nervous System Diseases; Chemicals; Clinical Trials; Cognitive; Deposition; Development; Disease; Dose; Drug Design; Drug Kinetics; Electrocardiogram; Electroencephalography; Enhancers; Event; Functional disorder; Future; Genetic; Grant; Heart; Human; Hyperactivity; Impaired cognition; In Vitro; Inflammation; Interneurons; Intervention; J20 mouse; Link; Liver Microsomes; Magnetism; Mediator of activation protein; Microglia; Molecular; Molecular Target; Monitor; Mus; Nerve Degeneration; Neurons; Oral Administration; Pathogenicity; Pathologic; Pathology; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Pre-Clinical Model; Property; Reporting; Role; Sensory; Series; Slice; Small Business Innovation Research Grant; Sodium Channel; Specificity; System; Toxic effect; Transplantation; Wild Type Mouse; base; cognitive function; design; drug candidate; drug development; efficacy testing; genome-wide; heart function; human disease; improved; in vivo; in vivo evaluation; intraperitoneal; mild cognitive impairment; mortality; mouse model; network dysfunction; neuropathology; neurovascular; novel; novel drug class; novel therapeutics; optogenetics; overexpression; patch clamp; phase 1 study; phase 2 study; pre-clinical; prevent; programs; restoration; screening; side effect; small molecule; small molecule therapeutics; stability testing; tau Proteins; tau aggregation; therapeutic target; transcriptome; transcriptomics; voltage

ABSTRACT CNDAP is developing a new class of drugs, acting through a unique mechanism of action, to reverse early pathophysiological and cognitive alterations in Alzheimer’s disease (AD). Recent studies indicate that network dysfunction, which includes network hyperactivity, altered oscillatory rhythms, and hyper- synchronized networks, is an early pathogenic event found in preclinical models of AD and in patients with early stages of AD. Network dysfunction contributes to cognitive abnormalities, Ab and tau accumulation, and neurodegeneration. In animal models, network dysfunction can be restored by enhancing inhibitory (GABAergic) interneuron-dependent gamma rhythms via optogenetic/sensory stimulation or genetic overexpression of Nav1.1. This restoration of gamma rhythms in the AD models leads to reduced amyloid and tau deposition, neurodegeneration, microglia and astrocytic activation, inflammation, neurovascular alterations, AD-induced genome-wide transcriptomics changes, altered oscillatory activity, and cognitive decline. Because overexpression of the sodium channel Nav1.1 by as little as 25% restores gamma rhythms to normal levels in AD models, we are developing small molecule therapeutics designed to safely increase Nav1.1 activity in the brain to treat AD. We have identified several small molecule chemotypes that effectively enhance human Nav1.1 currents in cell lines and interneuron-dependent gamma oscillations in brain slices. Systemic intraperitoneal administration of high doses of a Nav1.1 enhancer in vivo in mice produced no overt toxicity or behavioural side effects but significantly increased endogenous gamma oscillatory activity in wildtype mice, suggesting that our compounds are brain penetrant and may have beneficial effects following systemic administration. In this fast-track SBIR grant, we propose to further develop Nav1.1 enhancers to treat AD. In Phase 1 studies, we will employ medicinal chemistry and SAR analysis to identify structurally unique, potent and selective Nav1.1 enhancers to expand our chemical composition of matter. Pharmacokinetics and brain bioavailability analyses will be used to select the most active compounds with optimal pharmaceutical properties. Our milestone to achieve to move to Phase 2 studies is the identification of at least one structurally novel Nav1.1 enhancer that selectively and significantly increases gamma oscillations ex vivo in brain. Phase 2 studies are designed to establish the ex vivo and in vivo efficacy of our Nav1.1 enhancers to restore network dysfunction in preclinical AD mouse models by their ability to prevent network hypersynchrony and abnormal oscillatory activity, restore genome-wide transcriptomic changes and to reduce cognitive impairment, neuropathology and improve survival to support their future development to treat AD patients.

抽象的 CNDAP 正在开发一类新型药物，通过独特的作用机制发挥作用，以早期逆转 阿尔茨海默病（AD）的病理生理学和认知改变。最近的研究表明 网络功能障碍，包括网络过度活跃、振荡节律改变和过度兴奋 同步网络是在 AD 临床前模型和患有 AD 的患者中发现的早期致病事件 AD 的早期阶段。网络功能障碍导致认知异常、Ab 和 tau 蛋白积累，以及 神经变性。在动物模型中，网络功能障碍可以通过增强抑制来恢复 （GABAergic）通过光遗传学/感觉刺激或遗传的中间神经元依赖性伽马节律 Nav1.1 的过度表达。 AD 模型中伽马节律的恢复导致淀粉样蛋白减少 和 tau 沉积、神经变性、小胶质细胞和星形细胞激活、炎症、神经血管 改变、AD 诱导的全基因组转录组变化、振荡活动改变和认知 衰退。因为钠通道 Nav1.1 的过度表达仅 25% 即可恢复伽马节律 到 AD 模型中的正常水平，我们正在开发小分子疗法，旨在安全地增加 大脑中的 Nav1.1 活性可治疗 AD。我们已经确定了几种小分子化学型，可以有效地 增强细胞系中的人类 Nav1.1 电流和脑切片中神经元依赖性伽马振荡。 在小鼠体内全身腹膜内施用高剂量的 Nav1.1 增强剂没有产生明显的 毒性或行为副作用，但显着增加内源性伽马振荡活性 野生型小鼠，表明我们的化合物具有脑渗透性，并且可能在以下情况下产生有益作用： 全身给药。在这项快速 SBIR 拨款中，我们建议进一步开发 Nav1.1 增强剂 治疗AD。在第一阶段研究中，我们将采用药物化学和 SAR 分析来识别结构 独特、有效和选择性的 Nav1.1 增强剂可扩展我们的物质化学成分。 将使用药代动力学和脑生物利用度分析来选择最具活性的化合物 最佳的药物特性。我们实现进入第二阶段研究的里程碑是确定 至少一种结构新颖的 Nav1.1 增强剂，可选择性地显着增加伽马值 大脑离体振荡。第二阶段研究旨在确定我们的体外和体内功效 Nav1.1增强剂通过其预防的能力来恢复临床前AD小鼠模型中的网络功能障碍 网络超同步和异常振荡活动，恢复全基因组转录组变化和 减少认知障碍、神经病理学并提高生存率，支持他们的未来发展 治疗 AD 患者。