Grant: Operating Grant: Industry-partnered Collaborative Research - Other Partner

Therapeutic proteins are a new class of drug that has found success in several medical areas. Usually the protein is delivered, however the lifetime of the protein in the body can be very short (minutes), so that large quantities must be taken frequently. An alternative 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 systems to achieve this goal. We use a polymer of glucosamine, called chitosan, to bind to the DNA to form nanosized particles that deliver the DNA to cells. We have applied some of these chitosan-DNA nanoparticles to deliver glucagon-like peptide-1 (GLP-1) that is effective against diabetes. We have published 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 GLP-1 plasmids coding for modified GLP-1 peptides that resist enzymatic degradation and by delivering RNA molecules that inhibit the activity of the main enzyme degrading GLP-1, DPP-IV. These two approaches will increase the effectiveness of the peptide. An additional strategy is to modify the polymer chitosan to limit systemic clearance and produce longer circulating nanoparticles. The nanoparticles will be examined using model cells to assess delivery efficiency. Selected systems will be tested in the diabetic animal model for their efficacy in reducing diabetic signs and symptoms. The result of this project will be some promising new candidates for the treatment of diabetes ready to enter phase 1 clinical testing by the industrial partner of this project, Spencer Pharmaceuticals.