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）的发展是引起毒性的集体结果 通过β-淀粉样蛋白（Aβ）斑块，tau蛋白形成的神经原纤维缠结以及由于小胶质细胞的故障 炎症和氧化损伤。大多数广告疗法仅针对这些关键因素之一；失败的临床 试验提供了这些单独方法的不足。此外，尽管许多密钥抑制剂 AD中的分子靶标存在或可以轻松设计，98％的小分子，几乎全部 大分子无法有效地通过血脑屏障（BBB）。那就是能够治愈或 仍然无法轻松减轻AD症状。氧化岩纳米颗粒（CENP）充当金属 催化剂，表现出超氧化物歧化酶（SOD）和过氧化氢酶（CAT）模仿活动 有害细胞内活性氧（ROS）。我们的初步研究表明CENPS显示 出色的抗氧化剂和抗炎作用。但是，CENP的临床应用受到了阻碍 它的溶解度差，无法越过BBB。在神经炎症期间，晚期糖基受体 末端产物（愤怒）在BBB上过表达。这是这项研究的目的是开发广告大脑 通过使用BBB上的愤怒过表达和CENP的生物活性来实现的CENP。我们开发了 CENP添加的聚（乳酸 - 糖醇）（PLGA）纳米颗粒以克服药代动力学限制 自由CENP，并配备了靶向配体，以供愤怒接收器，以促进BBB渗透。我们的 初步数据表明，该广告大脑靶向CENP（T-CENP）可以有效地越过BBB，淬灭 升高的ROS，减弱小胶质细胞的激活，并减少AD小鼠中大脑中的Aβ燃烧 模型。在此STTR I期概念验证研究中，我们将验证我们的专有T-CENP的假设 可以通过两个特定目标开发为AD的新疗法。 SA1：评估毒性和 T-CENP在小鼠中的药代动力学特性。 T-CENP的最大耐受剂量（MTD）将首先 在C57BL/6J小鼠中确定；然后将在小鼠中检查T-CENP的药代动力学特性。 SA2：测试T-CENP的治疗效率，并在AD小鼠模型中评估其全身毒性。我们的 初步研究表明T-CENP在5xFAD AD小鼠模型中的效率。进一步验证T-CENP是否可以 用于AD处理，我们将评估T-CENP在3XTG-AD小鼠中的抗炎作用 显示AD​​的所有三个病理标志的模型，评估T-CENP在保护学习方面的影响 并使用莫里斯水迷宫测试和巢构建测定法对小鼠的记忆，并测量系统性 毒性。该阶段I项目完成后，我们将启动一个索引STTR II阶段项目以完成 在GLP环境中使用大型AD动物模型的更先进的毒理学和效率研究并进行 CGMP制造T-CENP用于人类使用。我们专有的广告脑针对性的交付技术也可以 用于交付其他不跨BBB但可能对AD治疗有效的药物。