The ultimate goal of the proposed work is to develop a novel co-formulation of insulin analogues (e.g. lispro and aspart) with an amylin analogue (e.g. pramlintide) to enable a transformational new treatment for diabetes constituting a true replacement therapy. The most challenging aspect of optimal glycemic control for the 1.25 million people with type 1 diabetes in the United States is limiting large increases in blood glucose after a meal. People with type 1 diabetes do not produce the insulin required for the body to process glucose, so insulin must be replaced by daily injections. Amylin is a small peptide hormone excreted alongside insulin by pancreatic ? islet cells that acts centrally to slow gastric emptying, suppress postprandial glucagon secretion, and decrease food intake, thus complementing the action of insulin to regulate blood glucose levels. Similar to insulin, amylin production is completely absent in individuals with type 1 diabetes on account of their lack of pancreatic ? cells. While treatment of diabetes with a combination of insulin and amylin analogues at meal times has been shown to be more effective than insulin alone, the burdensome administration of insulin and amylin analogues as two separate injections since these proteins can't be co-formulated. Symlin (Pramlintide; AstraZeneca), the only commercial amylin analogue formulation, is formulated at pH~4 while Novolog (Aspart; Novonordisk) and Humalog (Lispro; Eli Lilly), insulin analogue formulations, are typically formulated at pH~7.4. We have developed an approach to non-covalent PEGylation of proteins enabling stable co-formulation of these two drugs for the ?rst time whereby their optimal therapeutic ratio is de?ned in the formulation. This novel combination therapy will yield unprecedented postprandial glycemic control and catalyze the development of a powerful tool for the management of diabetes affording thus far unrealized therapeutic impact.

Public Health Relevance

The ultimate goal of the proposed work is to develop novel co-formulations of amylin analogues with insulin analogues to enable a true replacement therapy for treatment of diabetes. The most challenging aspect of optimal glycemic control in the treatment of diabetes is limiting large increases in blood glucose after a meal. Our novel combination therapy will yield unprecedented postprandial glycemic control and catalyze the development of a powerful tool for diabetes management affording thus far unrealized therapeutic impact.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK119254-01
Application #
9638988
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2019-01-15
Project End
2023-12-31
Budget Start
2019-01-15
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304