Targeted antibody-conjugated magnetic nanoparticles for the treatment of Alzheimer's disease

靶向抗体偶联的磁性纳米粒子用于治疗阿尔茨海默病

基本信息

批准号：
10314932
负责人：
Shen Ning
金额：
$ 5.05万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10314932
关键词：
3-Dimensional AD transgenic mice Acute Address Aducanumab Affect Aftercare Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease therapy American Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Antibodies Antibody titer measurement Behavioral Binding Blood - brain barrier anatomy Brain Cell Culture Techniques Cells Chronic Clinical Trials Communities Dementia Development Disease Disease Progression Dose Dot Immunoblotting Drug Delivery Systems Economic Burden Edema Electrophysiology (science)Excision Failure Frequencies Gel Human Image Immunoassay Immunofluorescence Immunologic Impaired cognition In Vitro Inflammatory Response Knowledge Magnetic Resonance Imaging Magnetic nanoparticles Magnetism Medical Memory Loss Methodology Methods Microelectrodes Microglia Modeling Neuraxis Neurofibrillary Tangles Neurons Normal Cell Nutrient Passive Immunization Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Phagocytes Pharmaceutical Preparations Physiological Prevalence Property Proteins Protocols documentation Public Health Safety Senile Plaques Signal Pathway Signal Transduction Structure Synapses Technology Testing Therapeutic Therapeutic Effect Therapeutic Uses Therapeutic antibodies Time Toxic effect Treatment Efficacy Western Blotting Work abeta accumulation abeta oligomer antibody conjugate arm base beta secretase blood-brain barrier crossing effective therapy efficacy testing efficacy validation extracellular gamma secretase humanized antibody hyperphosphorylated tau improved in vivo inflammatory marker iron oxide nanoparticle magnetic field morris water maze mouse model nanomedicine nanoparticle nervous system disorder neuroinflammation neuron loss novel novel therapeutics particle prevent side effect superparamagnetism symptom treatment tau Proteins tau-1 three dimensional cell culture

项目摘要

ABSTRACT/PROJECT SUMMARY Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive disturbances affecting over 5 million Americans. AD is hypothesized to be due to the accumulation of two pathogenic proteins in the brain. One is the accumulation of amyloid-β (Aβ) outside of cells and the second is the accumulation of hyperphosphorylated tau protein inside cells that eventually leads to aggregates called neurofibrillary tangles. The aggregation of amyloid prevents normal cell signaling pathways while neurofibrillary inhibit nutrient delivery to the neurons, both of which ultimately leads to neuronal death. Multiple AD previous clinical trials target pathogenic Aβ species using therapeutic anti-Aβ antibodies. However, previous failures in clinical trials demonstrate a gap in knowledge in our current understanding of the pathogenesis of AD and an immediate need for the development of new safe therapeutic approaches, which can be applicable at the very early stage of the disease. One major side effect in previous clinical trials is the chronic presence of high-titer anti-Aβ antibodies in brains triggers inflammatory responses and other undesirable side effects, namely amyloid- related imaging abnormalities including microhemorrhages (ARIA-H) and edema (ARIA-E). Since recent results from the aducanumab clinical trial is showing immense promise, there is an urgent need for the development of a technology to reduce these side effects. To address this challenge, which may contribute to the failures of these previous current drug trials, we developed superparamagnetic iron oxide nanoparticles conjugated with anti-Aβ antibodies that bind to Aβ peptides and aggregated Aβ species. These particles are paramagnetic, which allows them to be removed by an external magnetic field in vitro. To validate the efficacy and safety of anti-Aβ antibody conjugated SPIONs, we will use both 3D human neural cell culture models of AD, which our lab developed previously, and transgenic AD mouse models. Combining these two technologies, we devised a methodology to rapidly remove Aβ species using external magnetic force guided removal of anti-Aβ antibody conjugated SPIONs in 3D cell culture of AD. The 3D cell culture model will be mostly used for testing efficacy and the impact of the anti-Aβ antibody on Aβ-driven tau pathology while transgenic AD mice will be used to assess the efficacy and potential toxicity in vivo. Aim 1 evaluates the use of a static magnet with SPIONs with to reduce Aβ species in 3D culture model of AD and in an AD mouse model. The aim further investigates the downstream tau effects of Aβ removal in the 3D culture model. Aim 2 will examine the potential of using an alternating magnetic field to deliver therapeutic antibodies conjugated to SPIONs across the blood-brain barrier in the AD 5XFAD mouse model. This second aim has tremendous impact on the feasibility of this technology as a new therapeutic avenue not only for AD, but to deliver large molecule drugs for a variety of neurological diseases. Ultimately, the results of this work will lead to the potential development of a new therapy for AD as well as a new method for formulating and applying current AD drugs and therapeutics.

摘要/项目摘要阿尔茨海默病 (AD) 是最常见的痴呆症，其特征是进行性记忆丧失和影响超过 500 万美国人的认知障碍被重新认为是由于认知障碍的积累造成的。大脑中存在两种致病蛋白，一种是细胞外淀粉样蛋白 - β (Aβ) 的积累，另一种是细胞外的淀粉样蛋白 - β (Aβ) 的积累。是过度磷酸化的 tau 蛋白在细胞内的积累，最终导致称为聚集体淀粉样蛋白的聚集会阻止正常的细胞信号传导途径，而神经原纤维会发生缠结。抑制营养物质向神经元的输送，这两者最终都会导致神经元死亡。临床试验使用治疗性抗 Aβ 抗体针对致病性 Aβ 物种，但之前的失败。临床试验表明，我们目前对 AD 发病机制的理解存在知识差距，迫切需要开发新的安全治疗方法，这些方法可以立即适用先前临床试验中的一个主要副作用是该疾病的早期阶段长期存在高滴度。大脑中的抗 Aβ 抗体会引发炎症反应和其他不良副作用，即淀粉样蛋白 - 相关影像学异常，包括微出血（ARIA-H）和水肿（ARIA-E）。从 aducanumab 临床试验显示出巨大的前景，迫切需要开发减少这些副作用的技术可能会导致失败。在这些先前的当前药物试验中，我们开发了与与 Aβ 肽和聚集的 Aβ 物质结合的抗 Aβ 抗体这些颗粒具有顺磁性。允许它们在体外被外部磁场去除，以验证抗 Aβ 的有效性和安全性。抗体偶联的 SPION，我们将使用我们实验室的 AD 3D 人类神经细胞培养模型结合这两种技术，我们设计了一种转基因 AD 小鼠模型。使用外部磁力引导去除抗 Aβ 抗体快速去除 Aβ 物质的方法 AD 3D 细胞培养中的缀合 SPION 3D 细胞培养模型将主要用于测试功效。以及抗 Aβ 抗体对 Aβ 驱动的 tau 病理学的影响，同时转基因 AD 小鼠将用于评估体内功效和潜在毒性目标 1 评估静磁体与 SPION 的使用。减少 AD 3D 培养模型和 AD 小鼠模型中的 Aβ 种类。 3D 培养模型中 Aβ 去除的下游 tau 效应将检验使用 aβ 的潜力。交变磁场传递与 SPION 缀合的治疗抗体穿过血脑屏障在 AD 5XFAD 鼠标模型中，第二个目标对该技术的可行性产生了巨大影响。一种新的治疗途径，不仅可以治疗 AD，还可以为各种神经系统疾病提供大分子药物最终，这项工作的结果将导致开发出一种治疗 AD 的新疗法。以及制定和应用现有 AD 药物和疗法的新方法。