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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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/项目总结 阿尔茨海默氏病（AD）是最常见的痴呆形式，其特征在于进行性记忆丧失和 认知障碍影响了超过五百万美国人AD被假设为是由于 两种致病蛋白质一个是β淀粉样蛋白（Aβ）在细胞外的积累， 是过度磷酸化的tau蛋白在细胞内的积累，最终导致称为 神经系统缠结淀粉样蛋白的聚集阻止了正常的细胞信号通路， 抑制向神经元的营养传递，这两者最终导致神经元死亡。多个AD先前 临床试验使用治疗性抗A β抗体靶向致病性Aβ种类。然而，以前的失败， 临床试验表明，我们目前对AD发病机制的认识存在差距， 迫切需要开发新的安全的治疗方法，可适用于 疾病的早期阶段。在以前的临床试验中，一个主要的副作用是高滴度的慢性存在。 大脑中的抗A β抗体引发炎症反应和其他不良副作用，即淀粉样蛋白- 相关的影像学异常，包括微水肿（ARIA-H）和水肿（ARIA-E）。由于最近的结果 从aducanumab临床试验显示出巨大的希望，迫切需要开发 一种减少这些副作用的技术。为了应对这一挑战， 在这些先前的药物试验中，我们开发了超顺磁性氧化铁纳米颗粒， 与Aβ肽和聚集的Aβ物质结合的抗A β抗体。这些粒子是顺磁性的， 允许它们在体外被外部磁场去除。验证抗A β抗体的有效性和安全性 抗体结合SPION，我们将使用AD的3D人类神经细胞培养模型，我们的实验室 和转基因AD小鼠模型。结合这两种技术，我们设计了一种 使用外部磁力引导去除抗A β抗体快速去除Aβ物质的方法 在AD的3D细胞培养物中缀合SPION。3D细胞培养模型将主要用于检测疗效 以及抗A β抗体对Aβ驱动的tau病理学的影响，而转基因AD小鼠将用于 评估体内疗效和潜在毒性。目标1评价了静态磁铁与SPION的配合使用， 减少AD 3D培养模型和AD小鼠模型中的Aβ种类。目的是进一步研究 3D培养模型中Aβ去除的下游tau效应。目标2将研究使用 交变磁场以递送与SPION缀合的治疗性抗体穿过血脑屏障 在AD 5XFAD小鼠模型中。第二个目标对这项技术的可行性有着巨大的影响， 这是一种新的治疗途径，不仅适用于AD，而且适用于各种神经系统疾病的大分子药物。 疾病最终，这项工作的结果将导致AD新疗法的潜在发展， 以及配制和应用当前AD药物和治疗方法的新方法。