The development of a multifunctional nanoenzyme for AD treatment

用于AD治疗的多功能纳米酶的开发

• 批准号: 10611675
• 负责人: Peisheng Xu
• 金额: $ 29.96万
• 依托单位: ACEPRE, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10611675
• 关键词: 3xTg-AD mouse; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-Protein; Animal Model; Antiinflammatory Effect; Antioxidants; Area Under Curve; Attenuated; Biological Assay; Blood - brain barrier anatomy; Brain; Cause of Death; Clinical Trials; Cyclic GMP; Data; Deposition; Development; Disease; Dose; Drug Kinetics; Engineering; Exhibits; Glycolic-Lactic Acid Polyester; Half-Life; Healthcare; Human; In Vitro; Individual; Inductively Coupled Plasma Mass Spectrometry; Inflammation; Inflammatory Response; Injections; Investigational Drugs; Investigational New Drug Application; Learning; Ligands; Link; Maintenance; Maximum Tolerated Dose; Measures; Memory; Metals; Microglia; Mission; Molecular Target; Mus; Mutation; Names; Neurofibrillary Tangles; Pathologic; Pharmaceutical Preparations; Phase; Pilot Projects; Play; Process; Property; Reactive Oxygen Species; Research; Role; Safety; Senile Plaques; Small Business Technology Transfer Research; Solubility; Superoxide Dismutase; Surveys; System; Technology; Testing; Therapeutic; Toxic effect; Toxicology; Transgenes; United States; United States National Institutes of Health; blood-brain barrier penetration; catalase; catalyst; cerium oxide nanoparticle; clinical application; cost; design; drug candidate; efficacy study; improved; inhibitor; macromolecule; macrophage; morris water maze; mouse model; nanoparticle; nanoparticle delivery; neuroinflammation; novel therapeutics; overexpression; oxidative damage; presenilin-1; prevent; receptor for advanced glycation endproducts; reduce symptoms; safety testing; small molecule; success; systemic toxicity; targeted delivery; tau Proteins; therapeutic evaluation; therapy development; tool; β-amyloid burden

Summary. The development of Alzheimer’s disease (AD) is the collective consequence of the toxicities induced by β-amyloid (Aβ) plaques, tau protein-formed neurofibrillary tangles, and malfunction of microglia due to inflammation and oxidative damage. Most AD therapeutics only target one of these key factors; the failed clinical trials proved the insufficiency of these individual approaches. In addition, although many inhibitors of key molecular targets in AD either exist or could be easily designed, 98% of small molecules and almost all macromolecules cannot effectively pass through the blood-brain barrier (BBB). Thus, drugs capable of curing or stably alleviating the symptoms of AD are still not available. Cerium oxide nanoparticles (CeNPs) act as a metal catalyst, exhibiting both superoxide dismutase (SOD) and catalase (CAT) mimicking activities, which scavenges noxious intracellular reactive oxygen species (ROS). Our preliminary study revealed that CeNPs show outstanding antioxidant and anti-inflammatory effects. However, the clinical application of CeNPs is hindered by its poor solubility and inability to cross the BBB. During neuroinflammation, the receptor for advanced glycation endproducts (RAGE) is overexpressed on the BBB. Thus, the objective of this study is to develop an AD brain targeted CeNP by utilizing the RAGE overexpression on the BBB and the bioactivities of CeNP. We developed a CeNP-embedded Poly(lactide-co-glycolide) (PLGA) nanoparticle to overcome the pharmacokinetic limitation of free CeNP and equipped it with a targeting ligand for the RAGE receptor to facilitate BBB penetration. Our preliminary data demonstrates that this AD brain targeted-CeNP (T-CeNP) can effectively cross the BBB, quench the elevated ROS, attenuate the activation of microglia, and reduce Aβ burden in the brain in an AD mouse model. In this STTR Phase I proof-of-concept study, we will validate our hypothesis that our proprietary T-CeNP can be developed as a novel therapy for AD through two specific aims. SA1: Evaluate the toxicity and pharmacokinetic properties of T-CeNP in mice. The maximum tolerated dose (MTD) of T-CeNP will be first determined in C57BL/6J mice; and then the pharmacokinetic properties of T-CeNP will be examined in the mice. SA2: Test the therapeutic efficiency of the T-CeNP and evaluate its systemic toxicity in AD mouse models. Our preliminary study showed efficacy of T-CeNP in a 5xFAD AD mouse model. To further validate if T-CeNP could be used for AD treatment, we will evaluate the anti-inflammatory effects of the T-CeNP in a 3xTg-AD mouse model, which displays all three pathological hallmarks of AD, assess the effect of T-CeNP in protecting learning and memory of the mice using Morris water maze test and nest construction assay, and measure the systemic toxicity. Upon completion of this Phase I project, we will start an IND-enabling STTR Phase II project to complete more advanced toxicology and efficacy studies using large animal models of AD in a GLP setting and carry out cGMP manufacturing of T-CeNP for human use. Our proprietary AD brain-targeted delivery technology can also be used for the delivery of other agents that do not cross BBB but may be otherwise effective for AD treatment.

概括。阿尔茨海默氏病 (AD) 的发生是各种毒性反应的共同结果 β-淀粉样蛋白 (Aβ) 斑块、tau 蛋白形成的神经原纤维缠结以及小胶质细胞功能障碍 炎症和氧化损伤。大多数 AD 疗法仅针对这些关键因素之一；失败的临床 试验证明这些单独方法的不足。此外，尽管许多关键抑制剂 AD 中的分子靶点要么存在，要么很容易设计，98% 的小分子和几乎所有 大分子不能有效地通过血脑屏障（BBB）。因此，能够治愈或 目前还没有稳定缓解AD症状的方法。氧化铈纳米粒子 (CeNP) 作为金属 催化剂，表现出超氧化物歧化酶（SOD）和过氧化氢酶（CAT）模拟活性，可清除 有毒的细胞内活性氧（ROS）。我们的初步研究表明，CeNPs 显示 突出的抗氧化和抗炎作用。然而，CeNPs的临床应用受到以下因素的阻碍： 其溶解度差且无法穿过 BBB。在神经炎症期间，晚期糖化的受体 终产物 (RAGE) 在 BBB 上过度表达。因此，本研究的目的是开发 AD 大脑 利用 BBB 上的 RAGE 过表达和 CeNP 的生物活性来靶向 CeNP。我们开发了 CeNP 嵌入的聚丙交酯乙交酯 (PLGA) 纳米颗粒可克服药代动力学限制 游离的 CeNP 并为其配备 RAGE 受体的靶向配体，以促进 BBB 渗透。我们的 初步数据表明，这种AD脑靶向-CeNP（T-CeNP）可以有效穿过BBB，淬灭 升高的 ROS，减弱小胶质细胞的激活，并减少 AD 小鼠大脑中的 Aβ 负担 模型。在这项 STTR 第一阶段概念验证研究中，我们将验证我们的假设，即我们专有的 T-CeNP 可以通过两个特定目标开发为 AD 的新型疗法。 SA1：评估毒性和 T-CeNP 在小鼠体内的药代动力学特性。首先是T-CeNP的最大耐受剂量（MTD） 在 C57BL/6J 小鼠中测定；然后将在小鼠体内检查 T-CeNP 的药代动力学特性。 SA2：测试T-CeNP的治疗效率并评估其在AD小鼠模型中的全身毒性。我们的 初步研究显示 T-CeNP 在 5xFAD AD 小鼠模型中的功效。进一步验证T-CeNP是否可以 用于 AD 治疗，我们将在 3xTg-AD 小鼠中评估 T-CeNP 的抗炎作用 显示 AD 的所有三个病理特征的模型，评估 T-CeNP 在保护学习方面的效果 采用Morris水迷宫试验和筑巢试验对小鼠的记忆力和记忆力进行系统性测量 毒性。第一阶段项目完成后，我们将启动支持 IND 的 STTR 第二阶段项目，以完成 在 GLP 环境下使用大型 AD 动物模型进行更先进的毒理学和功效研究，并进行 人用 T-CeNP 的 cGMP 生产。我们专有的 AD 脑靶向递送技术还可以 用于输送不穿过 BBB 但可能对 AD 治疗有效的其他药物。