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.

阿尔茨海默氏病（AD）代表了美国和国外的主要慢性健康问题。 AD的MRI研究 表现出海马和与学习相关的其他大脑结构的大小的减小 和内存。像Aß和Tau这样的有毒蛋白在这些大脑区域中积累，MRS和PET成像 研究始终显示，代谢定义了AD患者大脑的氧化应激。 bdnf可以 改善新陈代谢，促进神经元可塑性并恢复大脑功能。但是，bdnf不能轻易 越过完整的血脑屏障（BBB），在血液中或口服时不稳定。在SBIR阶段1 ＆2，Exqor开发了一个纳米技术平台，该平台提供了一种创新的AD治疗方法。 由2个成分组成：网格蛋白纳米颗粒（CNP）和附着的脑源性神经营养因子 （bdnf）。 CNP成功绕过了鼻内（I.N.）和CNS浓度的血脑屏障（BBB） BDNF的BDNF高达400倍，比以前的BDNF I.N.报告高400倍。研究。 CNP恢复了内存和 通过增加神经发生，突触发生和树突完整性来再生海马区域 AD的鼠标模型。用两个不同的MR在小鼠海马中检测到CNP效应 神经影像的方式。基于体素的形态计量学显示CNP增强海马灰质 密度。质子MR光谱法表明，CNP降低了乳酸，丙氨酸，天冬氨酸，肌醇和肌酸降低 谷胱甘肽浓度，表明CNP逆转了厌氧代谢，神经胶质和氧化应激 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。 这项工作的目的是扩大生产BDNF-克拉蛋白纳米颗粒（CNP），执行 IND所需的药代动力学和安全性研究，并确认AD第二动物模型的效率。 在IIB SBIR中，一系列体内研究将确定CNP分布，安全性和效率。 TGF344-AD 在疾病过程中，将用CNP或安慰剂治疗大鼠6个月，并认知测试 MRI和1H MRS将在治疗后进行。我们计划展示这部小说的可行性 纳米技术以增强学习和记忆力，增加灰质密度并反向代谢 与AD相关的异常和氧化应激。 该研究项目将提供新的无创纳米技术工具，用于早期治疗AD。新的 纳米技术将能够增强神经元的代谢和可塑性，保护大脑并恢复大脑 与现有治疗方法相比，功能更快，更完全，同时使用较低的治疗方法 药物剂量并引起较少的副作用。稳定的靶向分子纳米颗粒的发展可能 还为AD中生物标志物研究提供了一个主要的新工具。这种小说的纳米技术可能是 可以专门针对相关大脑系统的下一代药物输送系统的基础，并且可以 具有实用性作为成像剂，以增强诊断和监测AD的进展。