Development and characterization of ultra-stable insulin analogs for novel therapeutic use

用于新型治疗用途的超稳定胰岛素类似物的开发和表征

• 批准号: 9259099
• 负责人: Nischay Kiran Rege
• 金额: $ 4.68万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259099
• 关键词: Adherence; Affinity; Amides; Amino Acid Sequence; Amyloid; Anabolism; Animal Model; Biochemistry; Biocompatible Materials; Biological; Biological Assay; Biomedical Engineering; Blood Glucose Self-Monitoring; Buffers; Cells; Characteristics; Chemicals; Circular Dichroism; Clinical; Cold Chains; Collaborations; Communities; Complement; Complex; Consult; Cystine; Development; Devices; Diabetes Mellitus; Disease; Disulfides; Doctor of Medicine; Doctor of Philosophy; Dose; Drug Delivery Systems; Drug Kinetics; Eating; Engineering; Enzyme-Linked Immunosorbent Assay; Evaluation; Exhibits; FDA approved; Formulation; Frequencies; Furuncles; Future; Glycolates; Gray unit of radiation dose; Health; Healthcare; Heating; High temperature of physical object; Hormone Receptor; Hormones; Hour; Hypoglycemia; Implant; In Vitro; Injection Site Reaction; Injection of therapeutic agent; Institutes; Insulin; Insulin Receptor; Insulin-Dependent Diabetes Mellitus; Insulin-Like-Growth Factor I Receptor; Intravenous; Intravenous Bolus; Isoelectric Point; Laboratory Study; Lectin; Letters; Life; Long-Acting Insulin; Longevity; Massachusetts; Measures; Medicine; Mentorship; Methods; Modeling; Modification; NMR Spectroscopy; Nature; Needles; Non-Insulin-Dependent Diabetes Mellitus; Oral; Outcome; Parents; Patients; Peptide Sequence Determination; Pharmacodynamics; Pichia; Pilot Projects; Polymers; Positioning Attribute; Predisposition; Prevalence; Property; Protein Engineering; Protein Isoforms; Proteins; Protons; Public Health; Rattus; Regimen; Replacement Therapy; Risk; Safety; Science; Scientist; Streptozocin; Structure; Students; Suspension substance; Suspensions; System; Technology; Temperature; Testing; Therapeutic Uses; Time; Training; United States; X-Ray Crystallography; Yeasts; analog; basal insulin; base; career; clinical care; design; diabetic; glucose monitor; glycemic control; health disparity; improved; improved outcome; interest; male; manufacturing process; melting; mid-career faculty; molecular dynamics; novel; novel therapeutics; pandemic disease; patient subsets; peptide hormone; potency testing; professor; resilience; subcutaneous; thermal stress; type I and type II diabetes

Diabetes mellitus poses a major public-health burden. Both in the United States and throughout the world, progressive increases have been observed in the prevalence of both Type 1 diabetes mellitus (T1DM) and Type 2 diabetes (T2DM). This application focuses on the development of thermodynamically stable insulin analogs that may be applied to novel drug-delivery systems. The applicant is an MSTP student who seeks training in biochemistry toward a future career that integrates clinical care with the development of novel therapeutics and devices. Clinical insulin regimens must compensate for the loss of regulated secretion by careful dosing coordinated with the patient's food intake, level of activity, and results of serial glucose monitoring. Adherence to such regimens requires self-injections several times a day. Such delivery methods not only cause discomfort for the patient, but they are also difficult to maintain in terms of timing and accurate administration of doses. The safety and efficacy of current regimens may be enhanced through the development of alternative mechanisms for insulin administration. Insulin's nature as a peptide hormone that is susceptible to chemical and temperature-induced degradation is a major barrier for its implementation in novel delivery systems. This application describes the combination of two previously characterized stabilizing modifications of the insulin hormone that will be used to create heat-stable insulin analogs that can be fabricated into PLGA- polymeric matrices and retain their biological activity. These insulin-infused polymers will be developed into microneedle implants that will serve as basal insulin delivery systems. These implants will reduce the frequency of self-injection while delivering safe, consistent, and continuous doses of insulin. Because of the interdisciplinary nature of the proposed studies, laboratory mentorship by the primary Thesis Advisor (M. Weiss, M.D., Ph.D.; Professor of Biochemistry, Biomedical Engineering & Medicine) will be complemented by a master clinician (diabetologist F. Ismail-Beigi, Professor of Medicine), an X-ray crystallography expert (V. Yee; Associate Professor of Biochemistry), and materials-scientist specializing in macromolecular sciences (J. Pokorski; Professor of Macromolecular Sciences). Additionally, consulting advisors D. Anderson and R. Langer, protein engineers at the Massachusetts Institute of Technology, will provide additional guidance on the development of the project.

糖尿病是一个重大的公共卫生负担。无论是在美国还是在全世界， 观察到1型糖尿病(T1 DM)和糖尿病的患病率都在逐渐增加 2型糖尿病(T2 DM)。这一应用重点是热力学稳定的胰岛素的开发 可应用于新型药物输送系统的类似物。申请人是一名MSTP学生，他寻求 生物化学方面的培训，面向未来的职业生涯，将临床护理与新药开发相结合 治疗学和设备。 临床胰岛素方案必须通过仔细协调的剂量来补偿调节分泌的丧失 根据患者的食物摄入量、活动水平和连续血糖监测结果。坚持这样的 养生法需要每天自我注射几次。这样的分娩方式不仅会给患者带来不适 但在时间安排和准确给药方面也很难维持。这个 目前方案的安全性和有效性可通过开发替代机制来提高 给他注射胰岛素。胰岛素的本质是一种多肽荷尔蒙，对化学和 温度引起的降解是其在新型递送系统中实施的主要障碍。 本申请描述了两个先前表征的稳定化修改的组合 胰岛素荷尔蒙将被用来产生热稳定的胰岛素类似物，可以被制造成PLGA- 聚合物基质，并保持其生物活性。这些注射了胰岛素的聚合物将被开发成 将作为基础胰岛素输送系统的微针植入物。这些植入物将减少 自我注射的频率，同时提供安全、一致和持续剂量的胰岛素。 由于拟议研究的跨学科性质，实验室辅导由主要论文 顾问(M.Weiss，医学博士；生物化学、生物医学工程和医学教授)将担任 辅以一名临床大师(糖尿病专家F·伊斯梅尔-贝吉，医学教授)，一名X光片 结晶学专家(V.Yee；生物化学副教授)，材料科学家，专门从事 高分子科学(J.Pokorski；高分子科学教授)。此外，咨询 麻省理工学院的蛋白质工程师顾问D.Anderson和R.Langer将 就项目的发展提供其他指导。