New BDNF Nanoparticles for Early Treatment of Alzheimer's Disease

阿尔茨海默病(AD)是美国和国外的一个主要的慢性健康问题。AD的MRI研究 显示出海马体和其他与学习相关的大脑结构的大小减少 和记忆。有毒蛋白质，如Aü和tau，在这些大脑区域积聚，MRS和PET成像 研究一直表明，AD患者的大脑存在代谢缺陷和氧化应激。脑源性神经营养因子可以 改善新陈代谢，促进神经元可塑性，恢复大脑功能。然而，BDNF不能轻易地 穿过完整的血脑屏障(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，为AD的治疗提供了一种创新的方法。它 由两个组分组成：一个网状蛋白纳米颗粒(CNP)和附着的脑源性神经营养因子 (BDNF)。CNPs经鼻腔成功绕过血脑屏障(BBB)。和中枢神经系统浓度 BDNF的数量比以前的BDNF I.N报告高出400倍。学习。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 阿尔茨海默病小鼠模型。用两种不同的MR在小鼠海马区检测到CNP效应 神经成像设备。基于体素的形态计量学显示CNP增强的海马灰质 密度。质子磁共振波谱显示，CNP降低乳酸、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、胶质增生和氧化应激 小鼠海马体。CNP还增加了与胆碱类化合物相关的增加 神经发生和神经元可塑性。 这项工作的目标是扩大BDNF-笼状蛋白纳米粒(CNPs)的生产， IND所需的药代动力学和安全性研究，并在第二个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。TgF344-AD 大鼠将在病程早期给予CNPs或安慰剂治疗6个月，并进行认知测试 治疗结束后行MRI和1HMRS检查。我们计划论证这部小说的可行性。 增强学习和记忆、增加灰质密度和逆转新陈代谢的纳米技术 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。新的 纳米技术将能够增强神经元的新陈代谢和可塑性，保护大脑，恢复大脑 比现有的治疗方法更快、更彻底地发挥作用，同时使用低得多的治疗方法 药物剂量大，副作用少。稳定、靶向的分子纳米颗粒的开发可能 也为AD生物标志物的研究提供了一个重要的新工具。这种新颖的纳米技术可能会成为 为下一代药物输送系统奠定基础，该系统可以专门针对相关的大脑系统，并可能 作为一种显像剂，可用于加强AD的诊断和监测进展。

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.