New BDNF Nanoparticles for Early Treatment of Alzheimer's Disease

用于早期治疗阿尔茨海默病的新型 BDNF 纳米颗粒

• 批准号: 10708092
• 负责人: GORDANA D. VITALIANO
• 金额: $ 99.6万
• 依托单位: EXQOR TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708092
• 关键词: 3xTg-AD mouse; Affect; Aftercare; Age Months; Agonist; Alanine; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Animal Disease Models; Animal Model; Animals; Antioxidants; Apoptosis; Aspartate; Biochemical; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain region; Brain-Derived Neurotrophic Factor; Bypass; Calcium; Canis familiaris; Cardiology; Cell Respiration; Cell Survival; Cell physiology; Cells; Choline; Chronic; Clathrin; Clinical Trials; Cognition; Cognitive; Complex; Data; Development; Diagnosis; Diet; Disease; Disease Progression; Dose; Down-Regulation; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Early treatment; Effectiveness; Exercise; FDA approved; Foundations; Free Radicals; Gliosis; Glucocorticoids; Glutamates; Glutathione; Goals; Health; Hippocampus; Impaired cognition; In Vitro; Inflammatory; Intranasal Administration; Learning; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maximum Tolerated Dose; Membrane; Memory; Memory impairment; Metabolic; Metabolism; Methods; Microglia; Modality; Molecular; Molecular Target; Monitor; Mus; N-Methylaspartate; Nanotechnology; Natural regeneration; Nerve Degeneration; Nerve Regeneration; Neuronal Plasticity; Neurons; Neuroprotective Agents; Nose; Oral; Organ; Oxidative Stress; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Placebos; Positron-Emission Tomography; Production; Proteins; Protons; Rattus; Recovery; Reporting; Research; Research Project Grants; Resolution; Safety; Saline; Scanning; Schedule; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Structure; Synapses; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Toxic effect; Toxicology; abeta accumulation; blood-brain barrier crossing; brain metabolism; brain volume; cognitive function; cognitive testing; crosslink; cytokine; density; detection method; drug candidate; gray matter; imaging agent; imaging modality; imaging study; improved; in vivo; in vivo magnetic resonance spectroscopy; innovation; intravenous administration; manufacturing scale-up; morphometry; mouse model; myoinositol; nanoparticle; nanoparticle delivery; nanotechnology platform; neurobehavioral; neurogenesis; neuroimaging; neuron loss; neuronal metabolism; neuropsychiatry; neurorestoration; neurotoxic; neurotrophic factor; next generation; non-invasive imaging; novel; pharmacokinetics and pharmacodynamics; pre-Investigational New Drug meeting; prevent; radiotracer; safety study; side effect; small molecule; socioeconomics; synaptogenesis; tau Proteins; tau aggregation; tool

Alzheimer's Disease (AD) represents a major chronic health problem in the US and abroad. MRI studies of AD demonstrated a decrease in the size of the hippocampus and other brain structures associated with learning and memory. Toxic proteins, like Aß and tau, accumulate in these brain regions, and MRS and PET imaging studies consistently showed metabolic deficits and oxidative stress in brains of patients with AD. BDNF can improve metabolism, promotes neuronal plasticity and restore brain functions. However, BDNF cannot easily cross an intact blood brain barrier (BBB) and is unstable in the blood or when delivered orally. In SBIR Phase 1 & 2, ExQor developed a nanotechnology platform that provides an innovative approach for treatment of AD. It consists of 2 components: a clathrin nanoparticle (CNP) and attached brain-derived neurotrophic factor (BDNF). CNPs successfully bypassed the blood-brain barrier (BBB) intranasally (i.n.) and CNS concentrations of BDNF were up to 400-fold higher than reported in previous BDNF i.n. studies. CNPs restored memory and regenerated hippocampal regions by increasing neurogenesis, synaptogenesis, and dendritic integrity in a mouse model of AD. CNP effects were detected in the mouse hippocampus with two different MR neuroimaging modalities. Voxel based morphometry showed CNP-enhanced hippocampal gray matter densities. Proton MR spectroscopy showed that CNP decreased lactate, alanine, aspartate, myoinositol and glutathione concentrations, indicating CNP reversed anaerobic metabolism, gliosis, and oxidative stress in the mouse hippocampus. CNP also increased choline-containing compounds associated with increased neurogenesis and neuronal plasticity. The goal of this effort is to scale-up production of BDNF-clathrin nanoparticles (CNPs), perform pharmacokinetic and safety studies required for IND, and confirm efficacy in the second animal model of AD. In Phase IIb SBIR, a series of in vivo studies will ascertain CNP distribution, safety and efficacy. TgF344-AD rats will be treated with CNPs or placebo early in the course of the disease for 6 months, and cognitive testing and MRI and 1H MRS will be performed after treatments. We plan to demonstrate the feasibility of this novel nanotechnology to enhance learning and memory, increase gray matter densities, and reverse metabolic abnormalities and oxidative stress associated with AD. This research project will provide new, noninvasive nanotechnology tools for early treatment of AD. The new nanotechnology will be able to enhance neuronal metabolism and plasticity, protect brain and restore brain functions more quickly and completely than existing treatment methods, while using much lower therapeutic drug doses and causing fewer side effects. The development of a stable, targeted molecular nanoparticle may also provide a major new tool for research of biomarkers in AD. This novel nanotechnology may serve as the basis for a next generation drug-delivery system that can specifically target relevant brain systems, and may have utility as an imaging agent to enhance diagnosis and monitor progression of AD.

阿尔茨海默病（AD）是美国和国外的主要慢性健康问题。AD的MRI研究 证明海马体和其他与学习相关的大脑结构的大小减少 和记忆有毒的蛋白质，如腺苷酸和tau蛋白，在这些大脑区域积累， 研究一致显示AD患者的脑中存在代谢缺陷和氧化应激。BDNF可以 改善新陈代谢，促进神经元可塑性和恢复大脑功能。然而，BDNF不能轻易地 穿过完整的血脑屏障（BBB），并且在血液中或口服时不稳定。在SBIR第1阶段 ExQor开发了一个纳米技术平台，为治疗AD提供了一种创新方法。它 由2种组分组成：网格蛋白纳米颗粒（CNP）和附着的脑源性神经营养因子 （BDNF）。CNP鼻内（i. n.）和CNS浓度 BDNF的表达比先前报道的BDNF i.n.问题研究CNP恢复了记忆， 通过增加海马中的神经发生、突触发生和树突完整性来再生海马区域 AD小鼠模型。在两种不同MR的小鼠海马中检测CNP效应 神经影像学方式。基于体素的形态测量显示CNP增强的海马灰质 密度质子磁共振波谱显示CNP降低了乳酸、丙氨酸、天冬氨酸、肌醇和 谷胱甘肽浓度，表明CNP逆转了无氧代谢，神经胶质增生和氧化应激。 小鼠海马。CNP还增加了与增加的含胆碱化合物 神经发生和神经元可塑性。 这项工作的目标是扩大BDNF-网格蛋白纳米颗粒（CNP）的生产， IND所需的药代动力学和安全性研究，并证实在AD的第二种动物模型中的疗效。 在IIb期SBIR中，一系列体内研究将确定CNP分布、安全性和疗效。TgF344-AD 在病程早期用CNP或安慰剂治疗大鼠6个月，并进行认知测试 治疗后行MRI和1H MRS检查。我们计划论证这部小说的可行性 纳米技术，以增强学习和记忆，增加灰质密度，并逆转代谢 与AD相关的异常和氧化应激。 该研究项目将为AD的早期治疗提供新的非侵入性纳米技术工具。新 纳米技术将能够增强神经元的代谢和可塑性，保护大脑和恢复大脑 比现有的治疗方法更快、更全面地发挥作用， 药物剂量和引起更少的副作用。稳定的靶向分子纳米颗粒的开发可以 也为AD生物标志物的研究提供了重要的新工具。这种新颖的纳米技术可能会成为 下一代药物输送系统的基础，可以专门针对相关的大脑系统， 具有作为成像剂以增强AD的诊断和监测其进展的效用。