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

糖尿病是一项重大的公共卫生负担。无论是在美国还是在世界各地，

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.