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.

总结。阿尔茨海默病(AD)的发生是各种毒物共同作用的结果 由β-淀粉样蛋白(Aβ)斑块、tau蛋白形成的神经原纤维缠结和小胶质细胞功能障碍引起的 炎症和氧化损伤。大多数AD疗法只针对这些关键因素中的一个；失败的临床 试验证明，这些单独的方法是不够的。此外，尽管许多关键的抑制剂 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的 大分子无法有效地通过血脑屏障(BBB)。因此，能够治愈或 稳定缓解阿尔茨海默病症状的方法仍不存在。氧化铈纳米颗粒(CeNPs)作为一种金属 具有超氧化物歧化酶(SOD)和过氧化氢酶(CAT)模拟活性的催化剂，其清除 有毒的细胞内活性氧(ROS)。我们的初步研究显示，CENPs显示 具有显著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 其溶解性差，不能通过BBB。在神经炎症期间，晚期糖基化的受体 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 通过利用血脑屏障上RAGE的过度表达和CENP的生物活性来靶向CENP。我们开发了 CENP包埋聚(丙交酯-乙交酯)(PLGA)纳米粒克服药代动力学限制 并为其配备了RAGE受体的靶向配体，以促进血脑屏障的渗透。我们的 初步数据表明，这种AD脑靶向CENP(T-CENP)可以有效地跨越血脑屏障，猝灭 阿尔茨海默病小鼠脑内ROS升高、小胶质细胞活化及A-β负荷减轻 模特。在这项STTRI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 可以通过两个特定的目的作为AD的一种新的治疗方法。SA1：评估毒性和 T-CENP在小鼠体内的药代动力学特性。T-CENP的最大耐受量(MTD)将是第一 在C57BL/6J小鼠体内测定，然后考察T-CENP在小鼠体内的药代动力学特性。 SA2：测试T-CENP的治疗效果，并评估其在AD小鼠模型上的全身毒性。我们的 初步研究表明，T-CENP对5xFAD小鼠模型有效。为了进一步验证T-CENP是否可以 用于治疗AD，我们将评估T-CENP在3xTg-AD小鼠身上的抗炎作用 显示AD所有三个病理特征的模型评估了T-CENP在保护学习方面的效果 并用Morris水迷宫实验和筑巢实验测定小鼠的记忆能力。 毒性。在此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环境中使用AD大型动物模型进行更高级的毒理学和有效性研究，并进行 人用T-CENP的cGMP制造。我们专有的AD脑靶向传递技术还可以 用于输送其他不跨越血脑屏障但可能对AD治疗有效的药物。