IL2-based Immunotherapy for Type 2 Diabetes

基于 IL2 的 2 型糖尿病免疫疗法

基本信息

批准号：
9135661
负责人：
RIDONG CHEN
金额：
$ 29.92万
依托单位：
APT THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9135661
关键词：
Adipose tissue Adverse effects Affinity Aldesleukin Amputation Animal Model Animals Antidiabetic Drugs Attenuated Binding Binding Sites Blindness Blood Blood Glucose Blood Vessels Body Weight CD8B1 gene Cancer Model Cardiovascular Diseases Cells Chimeric Proteins Chronic Diabetes Mellitus Diabetic mouse Diet Dose Eragrostis Escherichia coli Exhibits Family suidae Fatty acid glycerol esters Fructose Generations Goals Half-Life High Fat Diet Holidays Hospitalization Human IL2 gene IL2RA gene IL2RB gene IL2RG gene Immune Immunomodulators Immunotherapy In Vitro Inflammation Injection of therapeutic agent Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Interleukin-2 Investigational New Drug Application Kidney Kidney Failure Mammalian Cell Memory Metformin Modeling Mus Mutation Natural Killer Cells Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Omentum Overweight Patients Pharmaceutical Preparations Phase Phenotype Plasma Principal Investigator Recombinant Proteins Regulatory T-Lymphocyte Renal carcinoma Safety Serum Albumin Small Business Innovation Research Grant Syndrome T memory cell Therapeutic Toxic effect Validation Visceral Weight Gain Weight maintenance regimen Work abdominal fat abstracting base blood glucose regulation cytokine db/db mouse design diabetic eosinophil feeding glucose tolerance glycemic control immunogenic improved innovation insulin sensitivity melanoma molecular size mouse model novel novel strategies novel therapeutics prevent programs public health relevance receptor restoration success

项目摘要

DESCRIPTION (provided by applicant): Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong Abstract Type-2 diabetes (T2D) is a leading cause of cardiovascular disease, renal failure, blindness, amputations and hospitalization. Up to 80% of T2D patients are overweight or obese, which induces chronic, low-grade inflammation of adipose tissue and promotes insulin resistance and T2D. Moreover, weight gain is the common side-effect of older anti-diabetic drugs. Current therapies are not a cure and require daily administration. Hence, novel therapy that improves glucose control while simultaneously reducing body weight is urgently needed. CD4+CD25+Foxp3+ regulatory T cells (Treg) modulate inflammation and insulin resistance. Very interestingly, Treg cells with a unique phenotype are highly enriched in the visceral adipose tissue (VAT) of normal animals, but their numbers are strikingly and specifically reduced in insulin-resistant models of obese animals. Importantly, decreased numbers of Treg are also found in obese human omental. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of Treg by direct binding to its high affinity receptor. Hence, restoration of VAT Treg cells with low-dose IL2 may offer a novel strategy for mitigating obesity related low-grade inflammation and reversing insulin resistance and T2D. We have designed an IL2-based therapy that will enable selective stimulation of Tregs. In the proposed Phase I SBIR study, we will determine whether weekly treatment for 4 weeks leads to improvement of insulin sensitivity and glucose control, while reducing excessive body weight gain in the T2D models of obese db/db mice and diet-induced obese mice. The long-term goal of this project is to develop a novel treatment (weekly or bi-weekly) for T2D, alone or in combination with current therapies, to improve glucose homeostasis and attenuate diabetes-associated complications while simultaneously reducing excessive body weight gain.

描述（由申请人提供）：首席研究员/项目主任（姓、名、中：陈日东摘要 2 型糖尿病 (T2D) 是心血管疾病、肾衰竭、失明、截肢和住院的主要原因。最多 80 % 的 T2D 患者超重或肥胖，这会诱发脂肪组织的慢性、低度炎症，并促进胰岛素抵抗和 T2D。此外，体重增加是老年人常见的副作用。目前的治疗方法无法治愈糖尿病，因此迫切需要能够改善血糖控制并同时减轻体重的新疗法，以调节炎症和胰岛素抵抗。非常有趣的是，具有独特表型的 Treg 细胞在正常动物的内脏脂肪组织 (VAT) 中高度富集，但在肥胖动物的胰岛素抵抗模型中，它们的数量却显着减少。肥胖人网膜中也存在大量 Treg，白细胞介素 2 (IL-2) 是通过直接与其高亲和力受体结合而产生、存活和发挥 Treg 功能的关键细胞因子。因此，用低剂量 IL2 恢复 VAT Treg 细胞可能为减轻肥胖相关的低度炎症和逆转胰岛素抵抗和 T2D 提供一种新策略，我们设计了一种基于 IL2 的疗法，可以选择性刺激 Treg 细胞。在拟议的 I 期 SBIR 研究中，我们将确定每周治疗 4 周是否会改善胰岛素敏感性和血糖控制，同时减少肥胖 db/db 小鼠和饮食诱导肥胖的 T2D 模型中体重过度增加该项目的长期目标是开发一种新的 T2D 治疗方法（每周或每两周一次），单独或与现有疗法相结合，以改善葡萄糖稳态并减轻糖尿病相关并发症，同时减轻体重过重。获得。