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Glucagon-Like Peptide-1 Depots for the Treatment of Type-2 Diabetes

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Date
2012
Author
Amiram, Miriam
Advisor
Chilkoti, Ashutosh
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Abstract

Peptide drugs are an exciting class of pharmaceuticals currently in development for the treatment of a variety of diseases; however, their main drawback is a short half-life, which dictates multiple and frequent injections. We have developed two novel peptide delivery approaches -Protease Operated Depots (PODs) and GLP-1-ELP depots- to provide sustained and tunable release of a peptide drug from an injectable s.c. depot.

We demonstrate proof-of-concept of these delivery systems, by fusion of monomer or protease cleavable oligomers of glucagon-like peptide-1 (GLP-1), a type-2 diabetes peptide drug, and a thermally responsive, depot-forming elastin-like-polypeptide (ELP) that undergoes thermally triggered inverse phase transition below body temperature, thereby forming an injectable depot. Utilizing a novel system we designed for repetitive gene synthesis, various GLP-1 polymers were designed and tested as potential therapeutic payload for PODs. By attachment to various ELPs, designed to transition above or below body temperature, we created both depot forming GLP-ELP fusions and soluble control. All fusion constructs maintained alpha helical content and were shown to be resistant to proteolytic degradation. In vitro activated PODs and GLP-ELP fusions were able to activate the GLP-1 receptor and remarkably, a single injection of both GLP-1 PODs and GLP-ELP fusions were able to reduce blood glucose levels in mice for up to 5 days, 120 times longer than an injection of the native peptide drug. These findings suggest that ELP based peptide depots may offer a modular, genetically encoded alternative to various synthetic peptide delivery schemes for sustained delivery of peptide therapeutics.

Type
Dissertation
Department
Biomedical Engineering
Subject
Biomedical engineering
Drug Delivery
Elastin Like Polypeptides
Glucagon Like Peptide-1
Permalink
https://hdl.handle.net/10161/5499
Citation
Amiram, Miriam (2012). Glucagon-Like Peptide-1 Depots for the Treatment of Type-2 Diabetes. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/5499.
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