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

描述(申请人提供)：阿尔茨海默病(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。目前可用的治疗方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。尽管最初的临床试验在少数患者中出现了严重的不良反应，但免疫调节作为一种AD治疗方法显示出了巨大的前景。我们的研究小组假设刺激先天免疫系统可能是调节淀粉样蛋白和tau相关病理的替代方法，而没有相关的毒性。在我们的初步研究中，我们利用B型CpG ODN通过Toll样受体9(TLR9)在Tg2576 AD小鼠模型中刺激先天免疫系统，并表明这在减少实质和血管淀粉样蛋白负担以及与行为改善相关的A？寡聚体方面非常有效。此外，我们最近在三转基因(3xTg)AD小鼠中的发现证明，刺激TLR9信号具有同时解决A？和tau病理的优势。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患者和认知正常的老年人的共同特征。CAA是一种与年龄相关的脑血管疾病，导致人类20%的非创伤性脑出血。解决CAA问题成为确保免疫治疗成功的当务之急。我们的初步研究表明，CpG ODN治疗减少了CAA的病理，没有任何证据表明脑微出血增加。为了进一步评估未来人类对CpG ODN的任何潜在用途，我们计划在一个更接近生物学且已建立良好的散发性CAA的非人类灵长类动物模型-松鼠猴(Saimiri玻利维亚viensis)-中测试这种方法，并在CAA已经存在的情况下开始治疗。松鼠猴与人类的免疫学和血管相似性支持使用该模型来测试AD相关病理的新疗法，特别是CAA。设计治疗性疫苗的一个考虑因素是老年动物的免疫衰老。出于这个原因，我们最初的短期持续时间研究将在年轻猴子身上进行。对于我们在成年动物身上的长期研究，我们将选择具有最大有效性和安全性的剂量。总体而言，我们认为，建议的研究对于进一步优化这一新的免疫治疗方法，使CpG ODN更适合人类应用是至关重要的。

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.