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：
8531364
负责人：
Henrieta Scholtzova
金额：
$ 20.45万
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 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8531364
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（由适用提供）：阿尔茨海默氏病（AD）是全球最常见的痴呆症原因，具有重大的社会和经济影响。目前可用的疗法的认知能力下降最小，并且无法解决潜在的疾病发病机理。即使初步临床试验与少数患者的严重不良反应有关，免疫调节作为一种AD疗法表现出了很大的希望。我们的研究小组假定对先天免疫系统的模拟是调节淀粉样蛋白和TAU相关病理的可能替代方法，而无需相关的毒性。在最初的研究中，我们利用B CPG ODN型通过TG2576 AD小鼠模型中的Toll样受体9（TLR9）刺激先天免疫系统，并表明这对于减少副型和血管淀粉样淀粉样纤维燃烧非常有效，并与行为改善相关。此外，我们在三重转基因（3XTG）AD小鼠中的最新发现证明了TLR9信号传导的刺激具有同时解决A a和Tau病理的优势。免疫疗法的一个重大关注是清除血管淀粉样蛋白和相关的微型出血。这是一个重要的问题，因为脑淀粉样血管病（CAA）是AD和认知正常的患者的共同特征。 CAA是一种与年龄相关的脑血管疾病，在人类中导致20％的非创伤性脑出血。解决CAA的问题已成为确保免疫疗法成功的优先事项。我们的初步研究表明，CPG ODN治疗降低了CAA病理，而没有任何脑微听力增加的证据。为了进一步评估CPG ODN的任何潜在人类使用，我们计划在更接近生物学和良好建立的非人类私人模型的散发性CAA，Squirrel Monkey（Saimiri Boliviensis）中测试这种方法，并在已经存在CAA的时候开始治疗。松鼠猴子对人类的免疫学和血管相似性支持该模型用于测试与AD相关病理学的新兴疗法，尤其是CAA。设计治疗疫苗的一种考虑因素是老动物中的免疫性。因此，我们的最初短期持续时间研究将在年轻的猴子中进行。对于我们在成年动物中的长期研究，我们将选择具有最大效率和安全性的剂量。总体而言，我们认为拟议的研究对于进一步优化这种新型免疫治疗方法至关重要，以使CPG ODN更可行地使用CPG ODN。