Topical relief for painful diabetic neuropathy: Comparing CXCR4 small molecule inhibition and GM3 synthase spherical nucleic acid gene therapy

Painful diabetic neuropathy afflicts 25% of type 2 diabetics and is often associated with non-healing foot ulcers. We have uncovered clues to explain this sensory neuropathy, leading us to propose blocking or reversing neuropathy in diabetic foot skin with novel topically-applied medications engineered at Northwestern. One potently inhibits the CXCR4 chemokine receptor and the other uses nanotechnology to suppresses the gene that codes for ganglioside GM3 synthase (GM3S). Systemically-administered CXCR4 inhibitor and GM3S knockout prevent diabetic pain and skin nerve loss our type 2 diabetic mice, and both penetrate mouse footpad skin for topical delivery. We will apply the CXCR4 inhibitor and GM3S siRNA nanoconjugate to the hind footpads of diabetic mice with red fluorescent sensory nerves. We will compare the ability of these drugs to prevent and reverse diabetic pain and neuropathy through measuring footpad withdrawal pain thresholds (von Frey) and visualizing the nerves real-time (multiphoton imaging) and at sacrifice (confocal). If we can stabilize skin-based sensory innervation, we will plan clinical studies for our Northwestern Medicine diabetics at risk for neuropathy and foot ulcerations.