Diabetes has become a devastating epidemic worldwide. Insulin is commonly used as a treatment to help manage diabetes because of its ability to control blood glucose levels, and is in high demand worldwide, but it faces multiple challenges including adverse metabolic side-effects, short in vivo pharmaceutical life, and high cost. Today, millions of people continue to suffer and die from diabetes and its related conditions. Therefore, there is an urgent need to develop novel, inexpensive hypoglycemic agents to treat and arrest the fast spreading of this debilitating disease. A recombinant proinsulin-transferrin (ProINS-Tf) fusion protein was recently found to facilitate an enhanced and sustained in vivo hypoglycemic efficacy compared to insulin. While this fusion protein holds great promise as a novel hepato-specific hypoglycemic agent that can overcome some of the disadvantages of insulin, its therapeutic use is currently economically unfeasible due to low yields and high costs associated with its production in mammalian cell lines. In an effort to capture all the benefits of ProINS-Tf while lowering its supply cost, Ventria Bioscience and its collaborators at the University of Southern California are building on their respective expertise t express a ProINS-Tf chimeric protein in rice, and then assess its biological activities related to its usage as a novel hypoglycemic agent. This proposed project has three related specific aims. In Aim 1, Ventria will use its proprietary expression technology to transform rice plants with a chimeric gene construct composed of ProINS fused to Tf and will produce transgenic plants expressing ProINS-Tf. In Aim 2, Ventria will perform expression screening analysis to identify the transgenic events with the highest level expression of ProINS-Tf followed by protein purification. In Aim 3, Ventria's collaborators at the University of Southern California will confim the biological activities of ProINS-Tf through in vitro cell culture assays. The aims of these studies are to develop a novel and affordable hepatocyte prodrug for the treatment of diabetes. These studies are significant and relevant to the mission of the NIH to promote human health and reduce health care costs.
Public Health Relevance Statement: Public Health Relevance: Diabetes is the largest and fastest-growing chronic, disabling and deadly disease affecting young and old people worldwide. Insulin is the commonly used therapy for management of diabetes, but it faces multiple challenges including short in vivo pharmaceutical life, adverse metabolic side-effects, and high cost. There is an urgent need to develop novel, inexpensive hypoglycemic agents to treat and arrest the fast spreading of this debilitating disease. This project investigates the feasibility of using a plant-based expression system to cost- effectively produce a newly discovered recombinant proinsulin-transferrin fusion protein, which has been shown to enhance and sustain in vivo hypoglycemic efficacy compared to insulin. The outcome of this project will benefit the development of novel and affordable treatments for diabetes, and is significant and relevant to the mission of the NIH to promote human health and reduce the health care costs.
Project Terms: 20 year old; Adult; Adverse effects; Affect; Animals; base; Biodistribution; Biological; Biological Assay; Blood; Blood Glucose; California; Cell Culture Techniques; Cell Line; Cells; Cereals; Characteristics; chimeric gene; Chimeric Proteins; Chronic; Code; comparative efficacy; cost; cost effective; Defect; desensitization; Developing Countries; Development; diabetes management; Diabetes Mellitus; diabetic; Diagnosis; Disadvantaged; Disease; Dose; Drug Kinetics; Dyslipidemias; Embryo; Endocytosis; Enzyme-Linked Immunosorbent Assay; Epidemic; Event; Exhibits; Expenditure; Face; Financial cost; Fusion Protein Expression; Genes; Genome; glucose production; Grant; Growth; Half-Life; Health; Health Care Costs; Hepatocyte; hepatoma cell; Human; Hypoglycemia; Hypoglycemic Agents; In Transferrin; In Vitro; in vivo; Insulin; Insulin-Like Growth Factor I; Kidney; Life; Mammalian Cell; Measures; Medical; Metabolic; Methods; Mission; novel; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plants; Plasma; Process; Prodrugs; Production; Productivity; Proinsulin; protein purification; Proteins; Protocols documentation; public health relevance; Radioimmunoassay; receptor; receptor binding; receptor mediated endocytosis; Recombinant Fusion Proteins; Recombinants; Research; Rice; scale up; screening; Seeds; Small Business Innovation Research Grant; Somatotropin; Subcutaneous Injections; success; System; Technology; TF gene; Therapeutic; Therapeutic Uses; Toxic effect; Transferrin; Transgenic Organisms; Transgenic Plants; trend; United States National Institutes of Health; Universities; Western Blotting
