Grant: Operating Grant - PA: Inst of Nutrition, Metabolism and Diabetes -Bridge Funding

Therapeutic proteins are a relatively new class of drug that has found success in several medical areas. Usually the protein itself is delivered, however the lifetime of the protein in the body is very short, on the order of minutes, so that large quantities must be taken frequently. An alternative to delivering the protein is to deliver the DNA corresponding to the protein and allow the patient's cells to take up the DNA and make the corresponding protein. This gene delivery approach can be difficult since the DNA needs to be packaged in a way that allows cells to take it in, but also to unpackage the DNA once inside the cell and let it be transcribed into the protein. Recent work by our group has developed some very efficient polymer-based systems to achieve this goal. We use a polymer of glucosamine, called chitosan, to bind to the DNA to form nano-sized particles that deliver the DNA to cells. We have applied some of these chitosan-DNA nanoparticles to deliver a short protein, or peptide, that is effective against diabetes. This peptide, glucagon-like peptide 1 (GLP-1), acts at several points to lower circulating glucose and is known to be one of the most promising new candidates in the fight against diabetes. We have preliminary data showing that chitosan-DNA vectors expressing GLP-1 can lower circulating glucose in an animal model of diabetes, the ZDF rat. The proposed work aims to build upon this positive data by producing particles of specific sizes and stabilities, and increase their dose level. These nanoparticle gene-carrying systems will then be examined in vitro using different model cells lines to assess gene delivery efficiency and cell processing events. Finally selected systems will be tested in the diabetic animal model for their efficacy in reducing diabetic signs and symptoms, including circulating glucose levels. The net result of this project may be some promising new candidates for the treatment of diabetes type 2.