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

基本信息

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

项目摘要

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 AD MRI 研究的一个主要慢性健康问题。海马体和其他与学习相关的大脑结构的尺寸减小有毒蛋白质（如 Aß 和 tau）在这些大脑区域积聚，MRS 和 PET 成像。研究一致表明，BDNF 患者的大脑存在代谢缺陷和氧化应激。改善新陈代谢，促进神经元可塑性，恢复大脑功能，但BDNF却不容易。穿过完整的血脑屏障 (BBB)，在血液中或在 SBIR 第一阶段口服时不稳定。 2、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。由 2 个组件组成：网格蛋白纳米颗粒 (CNP) 和附着的脑源性神经营养因子 (BDNF) 成功绕过血脑屏障 (BBB) 鼻内 (i.n.) 和 CNS 浓度。 BDNF 的含量比之前 CNP 恢复记忆的研究中报道的高出 400 倍。通过增加神经发生、突触发生和树突完整性来再生海马区用两种不同的 MR 在小鼠海马中检测到 CNP 效应。基于体素的形态测量显示 CNP 增强的海马灰质。质子 MR 光谱显示 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 逆转了神经元中的无氧代谢、神经胶质增生和氧化应激小鼠海马的 CNP 也与含胆碱化合物的增加有关。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) 的生产规模， IND 所需的药代动力学和安全性研究，并在第二种 AD 动物模型中确认疗效。在 IIb 期 SBIR 中，一系列体内研究将确定 CNP 的分布、安全性和有效性。大鼠将在病程早期接受 CNP 或安慰剂治疗 6 个月，并进行认知测试我们计划在治疗后进行 MRI 和 1H MRS 来证明这种新颖的可行性。纳米技术可增强学习和记忆、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、非侵入性的纳米技术工具。纳米技术将能够增强神经代谢和可塑性，保护大脑和恢复大脑比现有的治疗方法更快速、更彻底地发挥作用，同时使用更低的治疗费用开发稳定的靶向分子纳米颗粒可能会减少药物剂量并减少副作用。这种新颖的纳米技术也为 AD 生物标志物的研究提供了一个重要的新工具。下一代药物输送系统的基础，该系统可以专门针对相关的大脑系统，并且可能具有作为显像剂的用途，可增强 AD 的诊断和监测进展。