Testing of Innate Immunity Stimulation via TLR9 on CAA using Non-human Primates.

使用非人类灵长类动物测试通过 TLR9 对 CAA 进行先天免疫刺激。

基本信息

批准号：
8359340
负责人：
Henrieta Scholtzova
金额：
$ 25.42万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8359340
关键词：
Acute Address Adult Adverse effects Agonist Allergic Alzheimer disease prevention Alzheimer&apos s Disease Amyloid Amyloid deposition Amyloidosis Animal Model Animals Attention Behavioral Biochemical Biochemistry Biological Biological Response Modifiers Blood Cell Count Blood Vessels Brain Diseases Brain hemorrhage Breeding Cells Cellular Immunity Censuses Cerebral Amyloid Angiopathy Cerebral hemisphere hemorrhage Cerebrum Clinical Trials Cognitive Collaborations Complication DNA Data Dementia Development Disease Dose Elderly Ensure Evaluation Family Future Goals Hemorrhage Hepatic Human Immune Immune response Immune system Immunologics Immunotherapeutic agent Immunotherapy Impaired cognition Individual Injection Site Reaction Knowledge Legal patent Ligands Longitudinal Studies Measures Methods Minority Modeling Monitor Monkeys Mus Natural Immunity Neurodegenerative Disorders Neurofibrillary Tangles New York Oligonucleotides Pathogenesis Pathology Patients Peripheral Peripheral Blood Mononuclear Cell Phenotype Population Preparation Prevention Prevention therapy Primates Prion Diseases Prions Problem Solving Protocols documentation Renal function Reporting Research Resources Risk Route Safety Saimiri Serum Signal Transduction Sporadic Cerebral Amyloid Angiopathy TLR9 gene Testing Texas Tg2576 Therapeutic Therapeutic Agents Therapeutic Uses Toll-like receptors Toxic effect Transgenic Organisms United States Universities Vaccination Vaccine Adjuvant Work age related aged base design dosage economic impact efficacy testing human Huntingtin protein immunoregulation immunosenescence mature animal meetings mouse model neoplastic nonhuman primate novel novel strategies prevent protein aggregate research clinical testing subcutaneous success synuclein tau Proteins therapeutic vaccine uptake

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is globally the most common cause of dementia with a significant societal and economic impact. Currently available therapies have a minimal effect of cognitive decline and do not address the underlying disease pathogenesis. Immunomodulation has shown great promise as an AD therapy, even though the initial clinical trial was associated with severe adverse effects in a minority of patients. Our research group postulated stimulation of the innate immune system as possible alternative method for modulating amyloid and tau related pathologies, without associated toxicity. In our initial studies we utilized type B CpG ODN to stimulate the innate immune system via Toll-like receptor 9 (TLR9) in the Tg2576 AD mouse model and showed this to be highly effective at reducing the parenchymal and vascular amyloid burden, along with A¿ oligomers, correlating with behavioral improvements. Moreover, our recent findings in the triple-transgenic (3xTg) AD mice document that stimulation of TLR9 signaling has the advantage of concurrently addressing both A¿ and tau pathologies. A significant concern with immunotherapy is clearance of vascular amyloid and associated microhemorrhages. This is an important issue, since cerebral amyloid angiopathy (CAA) is a common feature of patients with AD and cognitively normal elderly individuals. CAA is an age-related disorder of the brain vasculature that causes 20% of non-traumatic cerebral hemorrhage in humans. Solving the problem of CAA is becoming a priority for ensuring the success of immunotherapy. Our preliminary studies showed that CpG ODN treatment reduced CAA pathology without any evidence of increased cerebral microhemorrhages. To further assess any future potential human use of CpG ODN we plan to test this approach in a more biologically proximate and well established non-human primate model of sporadic CAA, squirrel monkey (Saimiri Boliviensis) and to begin treatment at a point where CAA is already present. Immunologic and vascular similarities of squirrel monkeys to humans support the use of this model for testing emerging therapies for AD related pathology, and CAA in particular. One consideration in designing therapeutic vaccines is immunosenescence in old animals. For this reason our initial short term duration studies will be performed in young monkeys. For our long term studies in adult animals we will select a dosage with the greatest efficacy and safety profile. Overall, we believe that the proposed studies are essential to further optimize this novel immunotherapeutic approach to make use of CpG ODN more feasible for human application.

描述（由申请人提供）：阿尔茨海默氏病（AD）是全球痴呆症的最常见原因，具有重大的社会和经济影响。目前可用的疗法对认知能力下降的影响很小，并且不能解决潜在的疾病发病机制。作为 AD 疗法，尽管最初的临床试验与少数患者的严重不良反应有关，但我们的研究小组假设刺激先天免疫系统是调节淀粉样蛋白和 tau 相关病理的可能替代方法，在我们的初步研究中，我们在 Tg2576 AD 小鼠模型中利用 B 型 CpG ODN 通过 Toll 样受体 9 (TLR9) 刺激先天免疫系统，并表明这对于减少实质和血管淀粉样蛋白负荷非常有效。，连同 A¿此外，我们最近在三重转基因 (3xTg) AD 小鼠中的发现表明，刺激 TLR9 信号传导具有同时解决 A¿免疫治疗的一个重要问题是清除血管淀粉样蛋白和相关的微出血，这是一个重要的问题，因为脑淀粉样血管病（CAA）是 AD 患者的一个常见特征，而认知功能正常的老年人也患有 CAA。导致人类 20% 非创伤性脑出血的脑血管系统相关疾病，解决 CAA 问题正在成为确保免疫治疗成功的首要任务。 CpG ODN 治疗减少了 CAA 病理，但没有任何增加脑微出血的证据。为了进一步评估 CpG ODN 未来人类使用的可能性，我们计划在生物学上更接近且完善的非人类灵长类散发性 CAA 模型（松鼠）中测试这种方法。松鼠猴（Saimiri Boliviensis）并在松鼠猴与人类已经存在 CAA 的免疫学和血管相似性时开始治疗，支持使用该模型进行测试。 AD 相关病理学的新兴疗法，特别是 CAA，设计治疗性疫苗时要考虑的一个因素是老年动物的免疫衰老，因此我们将在幼猴中进行长期研究。总体而言，我们认为所提出的研究对于进一步优化这种新型免疫治疗方法以使 CpG ODN 更适合人类应用至关重要。