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）：胰岛多肽（IAPP）沉积物中胰腺沉积物中约90％的2型糖尿病患者。淀粉样沉积的程度与胰岛素产生的β细胞的降低相关，表明这些淀粉样蛋白生成骨料或其低聚前体可能对β细胞有毒。该项目的目的是开发免疫疗法以清除这些沉积物和/或防止其形成。然后，这种方法可能会逆转或减慢糖尿病的进展和/或防止其发作。为此，将在维持其免疫原性的同时旨在非淀粉样蛋白酶的各种衍生物在体外表征，以确认其预测的二级结构和无毒特性。随后，将使用这些免疫原子接种胰腺淀粉样蛋白沉积物的人IAPP的转基因小鼠。在实验期间，将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担以及胰岛素水平以及相关的生化标记来评估这种治疗方法的功效。这种免疫疗法在其他淀粉样蛋白（例如阿尔茨海默氏症，prion-和帕金森氏病）的模型中已经成功。这些先前的发现支持该项目的可行性，目前尚无直接针对胰腺IAPP骨料的治疗。 目前，尽管仅诊断出约720万人，但在美国约有1600万人患有2型糖尿病，并且估计全球约有1.5亿次患有这种疾病。在超过90％的患有这种糖尿病的受试者中发现了胰岛多肽在胰腺中的沉积，这种肽在疾病的发作和进展中可能具有重要作用。我们提出的免疫治疗方法旨在清除和/或防止这些淀粉样蛋白沉积物的形成。我们和其他人在其他淀粉样蛋白疾病（例如阿尔茨海默氏症，prion-和帕金森氏病）中也取得了成功。这些研究可能导致2型糖尿病的新型治疗方法。