An Altered Peptide Ligand to Prevent Type 1 Diabetes

描述（由申请人提供） 1型糖尿病发生在遗传易感个体中， 胰腺进行性选择性破坏的结果 由自身反应性T细胞介导的β细胞。我们的长期目标是 了解1型糖尿病的自然史，并参加 评估预防或改善这种疾病的潜在新方法。 本申请的目的有三个：1）完成正在进行的 糖尿病预防试验-1型（DPT-1），2）参与设计和 实施新的干预策略，3）提出一种新的 干预策略，以测试改变的肽配体（APL）的影响， NBI-6024（神经分泌生物科学），在有临床1型风险的个体中 糖尿病这项拟议研究的中心假设是， 这种APL，含有两个来自胰岛素的天然L-氨基酸取代 B链（9-23）区，会缓和破坏性的自身免疫过程，导致 1型糖尿病，保护β细胞及其胰岛素分泌能力。 这项研究的基本原理是，如果用这种APL治疗是安全的， 有效阻止或减缓人群中疾病进展， 风险，它可以在糖尿病发展的早期阶段进行测试， 风险不太明确，可能导致大规模预防。我们 将测试我们提出的研究的中心假设，并完成 作为TriaINet临床中心的目标，通过追求以下三个 具体目标：1。完成DPT-1协议并实现其目标; 2. 建立合作研究者网络，参与设计 并开展进一步研究，以评估预防或 改善1型糖尿病，3.评估APL干预的效果 对1型糖尿病风险个体进展为临床糖尿病的影响。 我们期望DPT-1议定书将顺利完成， 并且胰岛素给药会改变破坏性的免疫反应， β-细胞，并减弱β-细胞自身免疫，从而预防或 1型糖尿病的治疗方法收集的数据也将 更好地描述1型糖尿病发展的自然史。 这也是我们的期望，基于我们的临床中心在 DPT-1，以及我们调查人员的专业知识，我们对 糖尿病TriaINet将有助于确保其成功实施， 促进其在未来干预试验中发挥预期作用。 此外，我们将测试我们的创新干预计划 基于APL NBI-6024的施用将预防或减少疾病 进展如果不加以预防， 功能在那些谁发展糖尿病将提供一个重要的临床 效益

DESCRIPTION (provided by applicant) Type 1 diabetes mellitus occurs in genetically predisposed individuals as a consequence of the progressive, selective destruction of the pancreatic beta-cells mediated by autoreactive T-cells. Our long-range goals are to understand the natural history of Type 1 diabetes and to participate in the evaluation of potential new approaches to prevent or ameliorate this disease. The objectives of this application are threefold: 1) to complete the ongoing Diabetes Prevention Trial-Type 1 (DPT-1), 2) to be involved in the design and implementation of new intervention strategies and, 3) to propose a novel intervention strategy, to test the effects of an altered peptide ligand (APL), NBI-6024 (Neurocrine Biosciences), in individuals at risk for clinical Type 1 diabetes. The central hypothesis of this proposed study is that administration of this APL, containing two natural L-amino acid substitutions from the insulin B-chain (9-23) region, will temper the destructive autoimmune process leading to Type 1 diabetes, preserving beta-cells and their insulin-secreting capacity. The rationale for this study is that, if treatment with this APL is safe and effective at stopping or slowing disease progression in a population at defined risk, it could be tested at an earlier stage of diabetes development, in those with less well-defined risk, and possibly result in large-scale prevention. We will test the central hypothesis of our proposed study and accomplish the objectives as a TriaINet Clinical Center by pursuing the following three Specific Aims: 1. Complete the DPT-1 protocols and achieve their objectives, 2. Establish a network of collaborating investigators to participate in the design and conduct of future studies to evaluate new approaches to prevent or ameliorate Type 1 diabetes, 3. Evaluate the effects of intervention with an APL on progression to clinical diabetes in individuals at risk for Type 1 diabetes. It is our expectation that the DPT-1 protocols will be successfully completed, and that insulin administration will alter the destructive immune response in the beta-cells, and attenuate beta-cell autoimmunity, thereby preventing or delaying the development of Type 1 diabetes. The data collected will also better characterize the natural history of Type 1 diabetes disease development. It is also our expectation, based on our Clinical Center performance in the DPT-1, and on the expertise of our investigators, that our contribution to the Diabetes TriaINet will help to ensure its successful implementation and facilitate its functioning as envisioned in future intervention trials. Additionally, we will test the hypothesis that our innovative intervention plan based on the administration of APL NBI-6024 will prevent or reduce disease progression. If not prevented, a treatment effect that preserves beta-cell function in those who do develop diabetes will provide an important clinical benefit.