Immunotherapy for Pancreatic Amylin Aggregates in Diabetes

糖尿病胰岛淀粉样蛋白聚集体的免疫治疗

• 批准号: 7387413
• 负责人: Einar M Sigurdsson
• 金额: $ 24.84万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7387413
• 关键词: Adjuvant; Adverse effects; Adverse reactions; Alzheimer Vaccines; Alzheimer' s Disease; Amyloid; Amyloid deposition; Amyloidosis; Animals; Antibodies; Antigens; Beta Cell; Biochemical Markers; Cell Count; Cells; Cerebrum; Clinical Trials; Cognition; Cytotoxic T-Lymphocytes; Deposition; Diabetes Mellitus; Diagnosis; Disease; Future; Goals; Human; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Inflammation; Inflammatory; Insulin; Insulin Resistance; Islets of Langerhans; Lead; Measures; Modeling; Molecular Conformation; Neuraxis; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Onset of illness; Pancreas; Parkinson Disease; Patients; Peptides; Personal Satisfaction; Preparation; Prevalence; Primates; Prions; Property; Proteins; Risk Factors; Role; Seeds; Structure; Symptoms; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; United States; Vaccinated; Vaccines; amyloid formation; amyloid peptide; conformer; design; diabetic; immunogenicity; improved; islet amyloid polypeptide; mouse model; novel; prevent; prophylactic; research study; response; success

DESCRIPTION (provided by applicant): Islet amyloid polypeptide (IAPP) deposits in the pancreas in about 90% of patients with type-2 diabetes. The extent of amyloid deposition correlates with the reduction in insulin producing beta-cells, indicating that these amyloidogenic aggregates or their oligomeric precursors may be toxic to beta-cells. The goal of this project is to develop immunotherapy to clear these deposits and/or prevent their formation. This approach may then reverse or slow the progression of diabetes and/or prevent its onset. Towards this end, various derivatives of IAPP, designed to be non-amyloidogenic while maintaining its immunogenicity, will be characterized in vitro to confirm their predicted secondary structure and non-toxic properties. Subsequently, transgenic mice for the human IAPP that develop pancreatic amyloid deposits will be vaccinated with these immunogens. The diabetic state of the animals will be assessed periodically during the experiment. At the end of the study, the efficacy of this treatment will be assessed by measuring beta-cell numbers and amyloid burden in the pancreas as well as insulin levels and related biochemical markers. This type of immunotherapy has been successful in models for other amyloidoses such as Alzheimer's-, prion- and Parkinson's disease as demonstrated by us and others. These prior findings support the feasibility of this project and there is currently no therapy available that directly targets pancreatic IAPP aggregates. Currently, about 16 million individuals in the United States are considered to have type-2 diabetes although only about 7.2 million have been diagnosed, and worldwide about 150 million are estimated to suffer from the disease. Deposition of islet amyloid polypeptide in the pancreas is found in over 90% of subjects with this form of diabetes and this peptide is likely to have a prominent role in disease onset and progression. Our proposed immunotherapeutic approach is designed to clear and/or prevent the formation of these amyloid deposits. We and others have had success with similar approaches in other amyloid diseases such as Alzheimer's-, prion-, and Parkinson's disease. These studies could lead to novel treatments for type-2 diabetes.

描述（由申请人提供）：胰岛淀粉样多肽（IAPP）沉积在约90%的2型糖尿病患者的胰腺中。淀粉样蛋白沉积的程度与产生胰岛素的β细胞的减少相关，表明这些淀粉样蛋白聚集体或其寡聚前体可能对β细胞有毒。该项目的目标是开发免疫疗法来清除这些沉积物和/或防止其形成。这种方法可以逆转或减缓糖尿病的进展和/或预防其发作。为此，IAPP的各种衍生物，设计为非淀粉样蛋白，同时保持其免疫原性，将在体外进行表征，以确认其预测的二级结构和无毒特性。随后，将用这些免疫原接种产生胰腺淀粉样蛋白沉积物的人IAPP转基因小鼠。在实验期间定期评估动物的糖尿病状态。在研究结束时，将通过测量胰腺中的β细胞数量和淀粉样蛋白负荷以及胰岛素水平和相关生化标志物来评估该治疗的疗效。这种类型的免疫疗法已经成功地用于其他淀粉样变性的模型，如阿尔茨海默氏病，朊病毒和帕金森氏病，正如我们和其他人所证明的那样。这些先前的发现支持该项目的可行性，并且目前没有直接靶向胰腺IAPP聚集体的可用疗法。 目前，美国约有1600万人被认为患有2型糖尿病，尽管只有约720万人被诊断出患有2型糖尿病，估计全世界约有1.5亿人患有这种疾病。在超过90%的患有这种形式的糖尿病的受试者中发现胰岛淀粉样多肽在胰腺中的沉积，并且这种肽可能在疾病的发作和进展中具有突出的作用。我们提出的免疫抑制方法旨在清除和/或预防这些淀粉样蛋白沉积物的形成。我们和其他人已经成功地用类似的方法治疗了其他淀粉样疾病，如阿尔茨海默病、朊病毒病和帕金森病。这些研究可能会导致2型糖尿病的新疗法。