PREVENTION OF TYPE I DIABETES BY FUSION PROTEINS

通过融合蛋白预防 I 型糖尿病

• 批准号: 6143125
• 负责人: YI None WANG
• 金额: $ 10万
• 依托单位: ALEXION PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6143125
• 关键词: biotherapeutic agent; chimeric proteins; disease /disorder prevention /control; drug design /synthesis /production; flow cytometry; immune tolerance /unresponsiveness; insulin dependent diabetes mellitus; laboratory mouse; laboratory rat; peptide chemical synthesis; protein engineering

Diabetes mellitus is associated with high morbidity and mortality as well as substantial financial cost. An estimated 1 million Americans have Type I diabetes, and the incidence of disease is approximately 15,000 new cases per year. Both animal models and human studies of autoimmune diabetes have demonstrated that antigen-specific T cells play a significant role in beta cell destruction. The aims of this proposal are to develop and characterize novel human insulin and GAD65 (IG) fusion proteins as reagents to induce antigen- specific T cell tolerance in Type I diabetes. In the Phase I study, we propose to (1) produce and characterize two fusion proteins termed IG2 and IG5, (2) functionally characterize the capacity of the IG2 and IG5 proteins to prevent the onset of type l diabetes in animal models, (3) evaluate the safety of lG fusion proteins, (4) analyze the mechanisms by which IG2 and IG5 proteins induce antigen-specific T cell tolerance in animal models. If this approach proves to be efficacious, we intend to select one of the two proteins as drug candidate in our Phase II proposal to explore the safety and efficacy of an IG protein treatment in the prevention of diabetes as well the treatment of new onset diabetic patients in Phase I clinical trials. Given the potential number of patients who could potentially benefit from a therapeutic agent that specifically blocks beta cell damage during autoimmune diabetes, the market for such a product represents a significant commercial opportunity. PROPOSED COMMERCIAL APPLICATIONS: Since approximately 1 million Americans have Type I diabetes, a pharmaceutical product capable of blocking beta cell damage during diabetes would be clinically significant, and address pharmaco-economic concerns.

糖尿病与高发病率和死亡率以及巨大的经济成本相关。估计有100万美国人患有I型糖尿病，并且疾病的发病率为每年约15，000个新病例。自身免疫性糖尿病的动物模型和人类研究都表明，抗原特异性T细胞在β细胞破坏中起重要作用。本提案的目的是开发和表征新型人胰岛素和GAD 65（IG）融合蛋白作为诱导I型糖尿病中抗原特异性T细胞耐受的试剂。在I期研究中，我们提出（1）产生并表征两种称为IG 2和IG 5的融合蛋白，（2）在功能上表征IG 2和IG 5蛋白在动物模型中预防I型糖尿病发作的能力，（3）评估IG融合蛋白的安全性，（4）在动物模型中分析IG2和IG5蛋白诱导抗原特异性T细胞耐受的机制。如果这种方法被证明是有效的，我们打算在我们的II期提案中选择两种蛋白质中的一种作为候选药物，以探索IG蛋白治疗在预防糖尿病以及在I期临床试验中治疗新发糖尿病患者中的安全性和有效性。考虑到可能受益于在自身免疫性糖尿病期间特异性阻断β细胞损伤的治疗剂的患者的潜在数量，这种产品的市场代表了重大的商业机会。拟议的商业应用：由于大约有100万美国人患有I型糖尿病，因此能够阻断糖尿病期间β细胞损伤的药物产品将具有临床意义，并解决药物经济问题。