Microparticle Therapy for Cerebral Amyloid Angiopathy

微粒治疗脑淀粉样血管病

基本信息

批准号：
10266159
负责人：
WOLFF M. KIRSCH
金额：
$ 111.95万
依托单位：
KARAMEDICA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10266159
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease therapeutic Amyloid Amyloid beta-Protein Anthrax disease Antigen-Antibody Complex Biopolymers Blood - brain barrier anatomy Blood Vessels Brain Brain hemorrhage Caliber Cell membrane Cells Cerebral Amyloid Angiopathy Cerebrovascular system Cerebrum Charge Chitin Chitosan Clinic Clinical Trials Code Cognitive Cognitive deficits Color Complement Complement Membrane Attack Complex Congresses Cytolysis Disease Drug Kinetics Elderly Elements Encapsulated Endotoxins Gene Expression Genes Glycoproteins Goals Hemorrhage Histocytochemistry Histologic Human Image Immunotherapy Impaired cognition In Vitro Infection Legal patent Letters Lipofectamine Magnetic Resonance Imaging Measurement Measures Mediating Membrane Methods Mus Nitrogen Nose Pathogenesis Phase Physiological Plasma Plasmids Play Polysaccharides Predisposition Prevalence Production Property Proteins Reproducibility Risk Risk Factors Role Secondary to Small Business Innovation Research Grant Smooth Muscle Myocytes Standardization Sterilization Surface System Techniques Technology Therapeutic Therapeutic Trials Time Transfection Transgenic Mice Transgenic Organisms Translations Treatment Efficacy Tunica Media Vascular Smooth Muscle apolipoprotein E-4 base cerebral microvasculature cerebrovascular clinically relevant cognitive performance cognitive testing complement system cryogenics effective therapy evidence base experience gene complementation gene delivery system improved in vivo microbial mouse model nano-string nanoparticle nanoparticle delivery neuropathology novel pharmacokinetics and pharmacodynamics pre-clinical preclinical trial prevent protective effect response stroke risk tomography zeta potential

项目摘要

PROJECT SUMMARY Cerebral Amyloid Angiopathy (CAA), a microvasculopathy in which beta-amyloid (Aβ) accumulates in the walls of cerebral blood vessels, is associated with vascular fragility and bleeding secondary to blood vessel wall breakdown. CAA is especially deleterious to vascular smooth muscle cells (VSMC). CAA is found in 70-90% of Alzheimer's disease (AD) cases, increases hemorrhagic stroke risk, and is exacerbated by active amyloid immunotherapy thereby compromising this promising AD therapeutic. There is no effective therapy for CAA. Despite the prevalence of CAA in AD and the fact that AD and CAA are different diseases, CAA is often overlooked in AD studies as Aβ has been widely presumed to be responsible for the VSMC loss in the walls of Aβ-laden vessels. VSMC loss in CAA occurs due to formation of the complement system's cytolytic membrane attack complex (MAC) in the tunica media of Aβ-laden CAA blood vessels. Based on this discovery by our scientific team, our goal is to develop a first-ever therapeutic for CAA based on inhibition of MAC formation which we hypothesize will prevent CAA-induced vascular fragility. We plan to target inhibition of MAC formation in the walls of Aβ-laden CAA blood vessels, as opposed to systemic MAC inhibition, due to the importance of MAC for immune protection against microbial infection. We propose a nose-to-brain nanoparticle therapy made of depyrogenated chitosan modified with diethylethylamine (DEAE) that delivers an encapsulated CD59 plasmid whose expression abrogates the formation of MAC. We have developed a technique to depyrogenate chitosan that enables internal placement since commercially available chitosans are contaminated with endotoxins. These contaminants interfere with plasmid transfection and gene expression. Our chitosan depyrogenation technique is based on the application of nitrogen plasma – the same technology employed to decontaminate potential anthrax letters sent to Congress after 9/11. We completed a Phase I SBIR in which we established successful transfection of primary human VSMCs with chitosan gene-containing nanoparticles, induced surface expression of CD59 in VSMCs via nanoparticle transfection, and established successful protection of CD59 transfected cells from MAC-initiated cell lysis. In this Phase II SBIR, we intend to (1) improve production of uniform, reproducible DEAE chitosan nanoparticles that are stable over time so as to achieve consistent, predictable in vivo transfection of brain microvasculature and provide parenchymal protection, (2) characterize the therapeutic efficacy of our nose-to-brain CS-CD59 nanoparticle CAA therapy in a relevant transgenic mouse model of CAA, and (3) determine histologic, physiologic, and cognitive effects in the transgenic CAA mouse model of enhanced CD59 expression. Successful completion of this project will help enable informed translation of our DEAE chitosan nanoparticle therapy for CAA into the clinic.

项目概要脑淀粉样血管病 (CAA)，一种 β-淀粉样蛋白 (Aβ) 在血管壁积聚的微血管病脑血管，与血管脆性和继发于血管壁的出血有关 CAA 对血管平滑肌细胞 (VSMC) 尤其有害。70-90% 的血管平滑肌细胞都存在 CAA。阿尔茨海默病 (AD) 病例会增加出血性中风的风险，并且活性淀粉样蛋白会加剧这种风险免疫疗法从而损害了这种有前途的 AD 治疗方法。目前还没有针对 CAA 的有效疗法。尽管 AD 中 CAA 很常见，而且 AD 和 CAA 是不同的疾病，但 CAA 常常在 AD 研究中被忽视，因为 Aβ 被广泛认为是导致血管壁 VSMC 损失的原因 CAA 中富含 Aβ 的血管由于补体系统溶细胞膜的形成而发生损失。基于我们的这一发现，Aβ 负载的 CAA 血管的中膜中存在攻击复合体（MAC）。科学团队的目标是开发出首个基于抑制 MAC 形成的 CAA 治疗方法，我们的目标是防止 CAA 引起的血管脆性，我们计划以抑制 MAC 的形成为目标。与全身性 MAC 抑制相反，由于 MAC 对 CAA 血管壁的重要性，我们提出了一种由鼻到脑的纳米颗粒疗法。用二乙基乙胺 (DEAE) 修饰的去热原壳聚糖，可传递封装的 CD59 质粒其表达消除了 MAC 的形成。我们开发了一种脱热原壳聚糖的技术。由于市售的壳聚糖被内毒素污染，因此可以进行内部放置。污染物会干扰我们的壳聚糖去热原技术。基于氮等离子体的应用——与净化潜力相同的技术 9/11 后，我们完成了第一阶段 SBIR，并成功建立了炭疽信函。用含壳聚糖基因的纳米颗粒转染原代人 VSMC，诱导表面表达通过纳米颗粒转染VSMCs中的CD59，并成功保护CD59转染的细胞在第二阶段 SBIR 中，我们打算 (1) 提高均匀、可重复的生产。 DEAE 壳聚糖纳米颗粒随着时间的推移保持稳定，从而在体内实现一致、可预测的效果转染脑微血管并提供实质保护，（2）表征治疗我们的鼻到脑 CS-CD59 纳米颗粒 CAA 疗法在相关 CAA 转基因小鼠模型中的功效， (3) 确定增强的转基因 CAA 小鼠模型的组织学、生理学和认知效应 CD59 表达的成功完成将有助于我们的 DEAE 的知情翻译。壳聚糖纳米粒子治疗CAA进入临床。