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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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，以早期逆转最近的研究表明，阿尔茨海默病（AD）的病理生理学和认知改变。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会导致认知异常、Ab 和 tau 蛋白积累以及在动物模型中，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 AD 模型中 Nav1.1 的过度表达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、振荡活动和认知因为钠通道 Nav1.1 的过度表达仅 25% 就能恢复伽马节律。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 活性可有效治疗 AD。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：在这项快速 SBIR 拨款中，我们建议进一步开发 Nav1.1 增强剂在第一阶段研究中，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药物特性是我们进入第二阶段研究的里程碑。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第二阶段研究旨在确定我们的离体和体内功效。 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。