Immune Therapy and Imaging in Mouse and Primate Models of Alzheimer's Disease.

阿尔茨海默病小鼠和灵长类动物模型的免疫治疗和成像。

• 批准号: 8676081
• 负责人: Einar M Sigurdsson
• 金额: $ 23.81万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2015-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676081
• 关键词: Active Immunization; Acute; Adverse effects; Adverse reactions; Affinity; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Antibodies; Antibody Therapy; Antigen-Antibody Complex; Antigens; Autopsy; Award; Behavior assessment; Behavioral; Biochemical; Blood; Blood Vessels; Brain; Brain imaging; Catalytic Antibodies; Cerebral Amyloid Angiopathy; Cerebrum; Chronic; Cleaved cell; Clinical; Clinical Trials; Cognition; Cognitive; Collaborations; Complex; Data; Deposition; Development; Dose; Encephalitis; Excision; France; Future; Glomerulonephritis; Grant; Hemorrhage; Homologous Gene; Human; Image; Immune response; Immune system; Immunization; Immunoglobulin G; Immunotherapy; Incidence; Inflammation; Inflammatory; Injection of therapeutic agent; Iron; Lemurs; Magnetic Resonance Imaging; Mediating; Methods; Modeling; Monitor; Monoclonal Antibodies; Mouse Lemur; Mus; Nature; Participant; Passive Immunization; Pathology; Patients; Plasma; Preparation; Primates; Property; Safety; Senile Plaques; Staging; T-Lymphocyte; Technology; Tg2576; Therapeutic; Therapeutic Effect; Toxic effect; Transgenic Mice; Treatment Efficacy; Urine; Vaccinated; Vaccination; Vaccines; Vasculitis; base; design; imaging probe; immunoregulation; improved; in vivo; mouse model; nonhuman primate; pre-clinical; research study; response; tau Proteins; tau aggregation; tau-1

DESCRIPTION (provided by applicant): Immune modulation to clear amyloid-beta (AB) is a promising therapy for Alzheimer's disease (AD). Although a clinical trial on this approach was recently halted because of T-cell related encephalitis in a small subset of patients, its preliminary findings indicate cognitive stabilization and clearance of brain AB deposits. During the first years of this grant, and prior to the adverse reactions in the trial, we have been assessing various AB derivatives as a safer approach for AD immunotherapy. All our vaccines improve cognition in transgenic (tg) mice indicating that these homologs are good candidates for clinical trials. Prior to this, non-human primate studies are warranted because their immune system and AB levels are closer to humans than the mouse equivalent. Hence, Specific Aim 1 is: To assess potential therapeutic benefits and side effects, in particular T-cell toxicity and cerebral bleeding, of AB derivative immunotherapy in lemur primates. We will determine: 1) the immune response; 2) AB levels in plasma and urine; 3) cognitive effects; 4) potential acute and chronic toxicity; and 5) brain amyloid burden and associated pathology following immunization with AB derivative immunogens in lemur primates (Microcebus murinus). In addition to histological and biochemical analysis at the end of the study, treatment efficacy and potential cerebral bleeding will be evaluated in vivo by brain imaging. We have developed MRI probes that allow us to detect brain amyloid plaques in vivo. This technology is ideally suited to monitor treatment efficacy in vivo. Because of the paramagnetic nature of iron, this method will also be useful to monitor potential cerebral bleeding. To avoid possible T-cell adverse effects, clinical AB antibody trials are underway but cerebral bleeding has been observed with this approach in tg mice. Specific Aim 2 is: A) To clarify the mechanism of cerebral microhemorrhages following AB antibody therapy and; B) To compare strategies to avoid this side effect while promoting AB clearance. Towards this end, tg mouse models that primarily develop vascular- or parenchymal AB deposits will be immunized with anti-AB antibodies or AB derivatives. Treatment efficacy and potential cerebral bleeding will be monitored with magnetic resonance imaging (MRI) and with histological and biochemical analyses at the end of the study. The animals will undergo extensive behavioral assessment as well. We will determine in tg mice if the bleeding is related to removal of vascular or parenchymal amyloid. Treatment with proteolytic antibodies that cleave AB is less likely to have this side effect, and we have not observed bleeding with our active immunization approach further supporting its feasibility for human use. Overall, these studies should provide valuable information on which type of immunotherapy is likely to be safe and effective, and should identify the appropriate AB-targeting immunotherapy for use in clinical trials.

描述（由申请人提供）：通过免疫调节清除β-淀粉样蛋白（AB）是阿尔茨海默氏病（AD）的一种有前途的疗法。尽管最近因一小部分患者出现 T 细胞相关脑炎而停止了该方法的临床试验，但其初步结果表明认知稳定并清除了大脑 AB 沉积物。在这笔资助的最初几年，在试验中出现不良反应之前，我们一直在评估各种 AB 衍生物作为 AD 免疫治疗的更安全方法。我们所有的疫苗都能改善转基因 (tg) 小鼠的认知能力，表明这些同系物是临床试验的良好候选者。在此之前，非人类灵长类动物的研究是必要的，因为它们的免疫系统和 AB 水平比小鼠更接近人类。因此，具体目标 1 是：评估 AB 衍生物免疫疗法在狐猴灵长类动物中的潜在治疗益处和副作用，特别是 T 细胞毒性和脑出血。我们将确定：1）免疫反应； 2) 血浆和尿液中的AB水平； 3）认知影响； 4）潜在的急性和慢性毒性； 5)狐猴灵长类动物（Microcebus murinus）用AB衍生免疫原免疫后的脑淀粉样蛋白负荷和相关病理学。除了研究结束时的组织学和生化分析外，还将通过脑成像在体内评估治疗效果和潜在的脑出血。我们开发了 MRI 探针，使我们能够在体内检测大脑淀粉样斑块。该技术非常适合监测体内治疗效果。由于铁的顺磁性，该方法也可用于监测潜在的脑出血。为了避免可能的 T 细胞副作用，临床 AB 抗体试验正在进行中，但在 tg 小鼠中观察到这种方法出现脑出血。具体目标 2 是：A) 阐明 AB 抗体治疗后脑微出血的机制； B) 比较避免这种副作用同时促进 AB 清除的策略。为此，主要产生血管或实质AB沉积物的tg小鼠模型将用抗AB抗体或AB衍生物进行免疫。在研究结束时，将通过磁共振成像（MRI）以及组织学和生化分析来监测治疗效果和潜在的脑出血。这些动物还将接受广泛的行为评估。我们将确定 tg 小鼠的出血是否与血管或实质淀粉样蛋白的去除有关。使用裂解AB的蛋白水解抗体治疗不太可能产生这种副作用，并且我们的主动免疫方法没有观察到出血，这进一步支持了其用于人类的可行性。总的来说，这些研究应该提供关于哪种类型的免疫疗法可能安全有效的有价值的信息，并且应该确定适当的 AB 靶向免疫疗法用于临床试验。

项目成果

New directions towards safer and effective vaccines for Alzheimer's disease.

开发更安全有效的阿尔茨海默病疫苗的新方向。

• 发表时间: 2005
• 期刊: Current opinion in molecular therapeutics
• 作者: Goñi,Fernando;Sigurdsson,EinarM
• 通讯作者: Sigurdsson,EinarM

Histological staining of amyloid-beta in mouse brains.

小鼠大脑中β-淀粉样蛋白的组织学染色。

• DOI: 10.1385/1-59259-874-9:299
• 发表时间: 2005
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Sigurdsson,EinarM

The three-panel runway maze adapted to Microcebus murinus reveals age-related differences in memory and perseverance performances.

适应鼠鼠的三板跑道迷宫揭示了记忆力和毅力表现与年龄相关的差异。

• DOI: 10.1016/j.nlm.2010.04.006
• 发表时间: 2010
• 期刊: Neurobiology of learning and memory
• 影响因子: 2.7
• 作者: Trouche,StephanieG;Maurice,Tangui;Rouland,Sylvie;Verdier,Jean-Michel;Mestre-Frances,Nadine
• 通讯作者: Mestre-Frances,Nadine

Age-associated evolution of plasmatic amyloid in mouse lemur primates: relationship with intracellular amyloid deposition.

• DOI: 10.1016/j.neurobiolaging.2014.07.017
• 发表时间: 2015-01
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Roy M;Cardoso C;Dorieux O;Malgorn C;Epelbaum S;Petit F;Kraska A;Brouillet E;Delatour B;Perret M;Aujard F;Dhenain M
• 通讯作者: Dhenain M

Age-associated cerebral atrophy in mouse lemur primates.

• DOI: 10.1016/j.neurobiolaging.2009.05.018
• 发表时间: 2011-05
• 期刊: NEUROBIOLOGY OF AGING
• 影响因子: 4.2
• 作者: Kraska, Audrey;Dorieux, Olene;Picq, Jean-Luc;Petit, Fanny;Bourrin, Emmanuel;Chenu, Evelyne;Volk, Andreas;Perret, Martine;Hantraye, Philippe;Mestre-Frances, Nadine;Aujard, Fabienne;Dhenain, Marc
• 通讯作者: Dhenain, Marc