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: 10325307
• 负责人: Michael Pleiss
• 金额: $ 44.98万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325307
• 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; Structure; 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正在开发一种新的药物，通过独特的作用机理起作用，以提早逆转 阿尔茨海默氏病（AD）的病理生理和认知改变。最近的研究表明 网络功能障碍包括网络多动症，振荡节奏改变和超级功能 同步网络是在AD的临床前模型中发现的早期致病事件， 广告的早期阶段。网络功能障碍会导致认知异常，AB和TAU积累，以及 神经变性。在动物模型中，可以通过增强抑制性来恢复网络功能障碍 （GABA能）通过光遗传学/感觉刺激或遗传 NAV1.1的过表达。 AD模型中γ节律的这种恢复导致淀粉样蛋白减少 和Tau沉积，神经退行性，小胶质细胞和星形细胞激活，感染，神经血管 改变，广告诱导的全基因组转录组学变化，振荡活性改变和认知 衰退。因为钠通道NAV1.1的过表达略低于25％ 在广告模型中，我们正在开发旨在安全增加的小分子疗法 NAV1.1大脑的活性以治疗AD。我们已经确定了几种有效的小分子化学型 增强人NAV1.1在细胞系中的电流和脑切片中依赖性的γ振荡。 全身性腹膜内施用高剂量的NAV1.1体内的NAV1.1增强剂在小鼠中没有产生明显的 毒性或行为副作用，但显着增加了内源性γ振荡活性 野生型小鼠，表明我们的化合物是脑渗透剂，可能具有有益的作用 系统管理。在这项快速跟踪的SBIR拨款中，我们建议进一步开发NAV1.1增强剂 治疗广告。在第1阶段研究中，我们将采用医学化学和SAR分析来识别结构 独特的，潜在的和选择性的NAV1.1增强剂，以扩展我们的物质化学成分。 药代动力学和脑生物利用度分析将用于选择最活跃的化合物 最佳药物特性。我们实现第二阶段研究的里程碑是识别 至少有一个结构新颖的NAV1.1增强剂，可有选择地并显着增加伽玛 大脑中的振荡。第2阶段的研究旨在建立我们的离体和体内效率 NAV1.1增强剂可以通过防止临床前AD鼠标恢复网络功能障碍 网络超同步和异常振荡活性，恢复全基因组的转录组变化和 减少认知障碍，神经病理学和改善生存，以支持其未来发展 治疗广告患者。