Immunotherapy for Pancreatic Amylin Aggregates in 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细胞的减少有关，这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/或防止它们的形成。这种方法可以逆转或减缓糖尿病的进展和/或预防其发病。为此，将对IAPP的各种衍生物进行体外表征，使其在保持免疫原性的同时不发生淀粉样变性，以证实其预测的二级结构和无毒特性。随后，产生胰腺淀粉样蛋白沉积的人类IAPP转基因小鼠将接种这些免疫原。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指标来评估这种治疗的疗效。这种类型的免疫疗法已经在其他淀粉样病变的模型中取得了成功，如阿尔茨海默病、朊病毒病和帕金森病，正如我们和其他人所证明的那样。这些先前的发现支持了该项目的可行性，目前还没有直接针对胰腺IAPP聚集体的治疗方法。

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.