Microparticle Therapy for Cerebral Amyloid Angiopathy

微粒治疗脑淀粉样血管病

• 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
• 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' s Disease; Alzheimer' 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

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.

项目摘要 脑淀粉样蛋白血管病（CAA），一种微甲虫病，其中β-淀粉样蛋白（Aβ）积聚在壁上 脑血管的血管与血管脆弱性和流血壁的出血有关 分解。 CAA对血管平滑肌细胞特别细腻（VSMC）。 CAA在70-90％中发现 阿尔茨海默氏病（AD）病例，增加了出血性中风风险，并因活性淀粉样蛋白而加剧 免疫疗法因此损害了这种有希望的AD疗法。 CAA没有有效的疗法。 尽管AD中CAA的流行率以及AD和CAA是不同疾病的事实，但CAA通常是 在AD研究中被忽略为Aβ已被广泛预览，以造成VSMC损失 载有Aβ的血管。 CAA中的VSMC丢失是由于完成系统的细胞溶解膜的形成而发生的 载有Aβ的CAA血管的Tunica培养基中攻击复合物（MAC）。基于我们的发现 科学团队，我们的目标是基于抑制MAC形成的CAA的首个疗法 我们假设将防止CAA引起的血管脆弱性。我们计划靶向对MAC形成的抑制 载有Aβ的CAA血管的壁，与全身性MAC抑制相反，由于MAC的重要性 免疫防止微生物感染。我们提出了一种由 用二乙基乙胺（DEAE）修饰的去阳性壳聚糖可提供封装的CD59质粒 其表达废除了MAC的形成。我们已经开发了一种技术来抑制壳聚糖 这可以实现内部放置，因为市售的壳聚糖被内毒素污染。这些 污染物干扰质粒翻译和基因表达。我们的壳聚糖部署技术 是基于氮等离子体的应用 - 相同的技术用于净化潜力 9/11之后，炭疽信件发送给国会。我们完成了I阶段的SBIR，我们在其中建立了成功 用含壳聚糖基因的纳米颗粒转染原代人VSMC，诱导表面表达 通过纳米颗粒转染在VSMC中的CD59，并成功保护了CD59转染的细胞 来自MAC引起的细胞裂解。在此II阶段SBIR中，我们打算（1）改善均匀，可重复的生产 随着时间的推移稳定的DEAE壳聚糖纳米颗粒，以实现一致的，可预测的体内 脑微举行的转染并提供实质保护，（2）特征是治疗性的 我们的鼻 - 脑CS-CD59纳米粒子CAA疗法的功效在CAA的相关转基因小鼠模型中 （3）在增强的转基因CAA小鼠模型中确定组织学，生理和认知效应 CD59表达。该项目的成功完成将有助于实现我们的DEAE的知情翻译 CAA进入诊所的壳聚糖纳米粒子疗法。