Diabetes is exploding globally and in the US, driven by an increasingly sedentary life-style, poor nutritional habits and obesity. It has been estimated that type-2 diabetes will soon assume a pandemic status globally. An analog of glucagon-like peptide-1 (GLP-1), Exenatide, is an approved drug to treat type-2 diabetes in humans. However, both GLP-1 and Exenatide are rapidly cleared, which necessitates twice-daily injection of the drug, and also leads to undesirable side-reactions such as nausea, and hence limits both the efficacy of the drug and its widespread adoption. Longer acting formulations of GLP-1 analogs and other peptide drugs are hence needed to improve drug efficacy and increase patient compliance. Motivated by this rationale, the overall objective of this proposal is to develop a novel biomaterials platform technology to enhance the half-life of GLP-1, by the in vivo formation of an injectable drug depot, which we have named Protease Operated Depots (PODs). Our design of PODs is implemented by the fusion between a thermally sensitive elastin-like polypeptide (ELP) that is soluble at room temperature but forms a viscous coacervate depot upon injection at body temperature, and repeats of GLP-1 that have recognition sites for a specific protease, embedded between repeats of the peptide drug. This strategy leverages our previous experience in biomaterials development of recombinant ELP-based biopolymers that can be designed to undergo a phase transition in vivo, driven by body heat to form a highly viscous coacervate with long retention upon injection.
The specific aims are: (1) to synthesize a library of PODs with varied ELP MW and transition temperature, number of GLP-1 repeats per oligomer, and different protease recognition sequence between the GLP-1 repeats;(2) investigate the in vivo pharmacokinetics of PODs in a mouse model of type-2 diabetes to identify a subset of PODs that may be useful for once-a-week and once-a-month injection;and (3) carry out in vivo efficacy studies of a subset of these PODs. The outcome of these studies will be demonstration of PODs for the sustained delivery of GLP-1 with tunable injection frequency, as dictated by clinical need. Given the rise of type-2 diabetes in children and adolescents, an injectable formulation of GLP-1 that can be injected subcutaneously through a narrow gauge needle with a once-a-week or preferably once-a-month duration of efficacy, as proposed here will, we believe, also provide the necessary attributes for effective treatment of this sub-population of patients. More broadly, we envision PODs as a broadly applicable biomaterials platform technology to improve the pharmacokinetics and bioavailability, and hence efficacy of a large subset of peptide drugs that are currently in the clinical pipeline.

Public Health Relevance

The proposed research will develop Protease Operated Depots (PODs), a new biomaterials platform for sustained release of peptide drugs. We will show that injection of a POD of glucagon-like peptide (GLP-1), a peptide drug that is used for treatment of type-2 diabetes, below the skin leads to formation of a depot, and that this depot slowly releases the active peptide drug over a specified period of time that we can tune by design of the POD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091789-02
Application #
8447002
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Pawlyk, Aaron
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$320,968
Indirect Cost
$111,080
Name
Duke University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Amiram, Miriam; Luginbuhl, Kelli M; Li, Xinghai et al. (2013) Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control. Proc Natl Acad Sci U S A 110:2792-7
Amiram, M; Luginbuhl, K M; Li, X et al. (2013) A depot-forming glucagon-like peptide-1 fusion protein reduces blood glucose for five days with a single injection. J Control Release 172:144-51