Metabolic syndrome (MetS), affects more than 50 million people in the US alone. The current standard of care embodies polypharmacological therapies that are mostly directed at controlling individual risk factors of MetS (e.g. lipid altering agents, anti-hypertensives, and insulin sensitizers), but most of these treatments do not target underlying pathological mechanisms. Consequently, there is high unmet need to develop an innovative therapy that ultimately prevents cardiovascular morbidity and mortality by targeting major pathophysiological mechanisms, normalizing or improving metabolic syndrome risk factors, and reversing type 2 diabetes (T2D). CD4+CD25+Foxp3+ regulatory T cells (Treg) modulate inflammation and insulin resistance. Treg cells are highly enriched in the visceral adipose tissue (VAT) of normal animals, but their numbers are reduced in insulin-resistant models of obese animals. Importantly, decreased numbers of Tregs are also found in obese human omentum. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of Tregs by direct binding to its high affinity receptor. Treatment with low-dose (1-3% cancer model dose) rIL-2 increases anti-inflammatory Treg cells and M2 type macrophages and inhibits pathogenic interferon-? secreting T helper type 1 cells in the abdominal fat, leading to improvement in glucose tolerance and insulin sensitivity in mice on a high fat diet. Moreover, IL2 turns unhealthy white fat into beneficial brown fat. Hence, restoration of VAT Treg cells and “browning” with low-dose IL-2 may offer a novel strategy for prevention and treatment of T2D and the reduction of cardiovascular disease. However, several drawbacks exist for current low-dose rIL-2 therapy, including a short half-life, propensity to in vitro aggregation causing adverse local reaction at injection sites, and a potentially narrow therapeutic window. We have designed a proprietary IL-2 fusion therapy with multiple functions and a broad therapeutic window. In the proposed Phase I SBIR study, we will determine whether weekly treatment of the fusion therapy for 12 weeks will effectively reverse the major risk factors of MetS and type 2 diabetes in ZDSD rats continuously fed a high fat and carbohydrate diet. The long-term goal of this project is to develop an innovative and global treatment for MetS and diabetes.
Public Health Relevance Statement: Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong Narrative: The proposed approach will decrease the risk for cardiovascular disease by treating the underlying metabolic disease and type 2 diabetes with weekly doses of a novel immunomodulator and insulin stimulator.
Project Terms: abdominal fat; Adipose tissue; Affect; Affinity; Aldesleukin; Animal Model; Animals; Anti-Inflammatory Agents; Antibodies; Antidiabetic Drugs; Antihypertensive Agents; Atherosclerosis; attenuation; Binding; Binding Sites; Blood; Blood Glucose; blood glucose regulation; Blood Pressure; Blood Vessels; Body Weight; Brown Fat; Cancer Model; Carbohydrates; Cardiovascular Diseases; cardiovascular disorder risk; Cardiovascular system; CD8-Positive T-Lymphocytes; Cells; Central obesity; Chimeric Proteins; Complications of Diabetes Mellitus; cost; cytokine; Data; design; Development; Diabetes Mellitus; diabetic; Diet; Dilated Cardiomyopathy; Dose; Dyslipidemias; effector T cell; eosinophil; Eragrostis; Escherichia coli; Event; Family suidae; Fatty acid glycerol esters; FDA approved; FOXP3 gene; Fructose; Generations; glucagon-like peptide 1; glucose tolerance; Goals; Half-Life; Heart failure; High Fat Diet; Human; Hyperglycemia; Hyperinsulinism; Hypertension; IL2 gene; IL2RA gene; IL2RB gene; IL2RG gene; Immune; immunogenic; Immunomodulators; improved; In Vitro; Individual; Inflammation; Injection Site Reaction; Injections; innovation; Innovative Therapy; Insulin; Insulin Resistance; insulin sensitivity; insulin sensitizing drugs; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-2; Investigational New Drug Application; Ischemic Stroke; Kidney; Leptin; Lipids; macrophage; Mammalian Cell; melanoma; Memory; Metabolic Diseases; Metabolic syndrome; Modeling; molecular size; Monkeys; Morbidity - disease rate; mortality; Mus; Mutation; Myocardial Infarction; Myocarditis; Natural Killer Cells; Non-Insulin-Dependent Diabetes Mellitus; Nonlytic; Normal tissue morphology; novel; novel strategies; Obese Mice; Obesity; Omentum; Pathogenicity; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Play; Prediabetes syndrome; prevent; Prevention strategy; Principal Investigator; programs; protein E; Rattus; Reaction; receptor; Recombinants; Regulation; Regulatory T-Lymphocyte; Renal carcinoma; restoration; Risk Factors; Role; Safety; Serum Albumin; side effect; Site; Small Business Innovation Research Grant; standard of care; success; Syndrome; Th1 Cells; Therapeutic; Toxic effect; Triglycerides; Variant; Ventricular Remodeling; Visceral; Work
