Soluble Receptor for Advanced Glycation End Products for Therapeutic Application

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Cellular signaling via receptor for advanced glycation end products (RAGE) results in pro-inflammatory responses. RAGE-mediated inflammation has been implicated in inflammatory diseases including diabetes, atherosclerosis, Alzheimers disease. The spliced or proteolytically cleaved form of RAGE is referred as soluble RAGE (sRAGE), which functions as a natural decoy counter-effecting RAGE signaling. It has been demonstrated in animal models that administration of sRAGE blocks atherogenesis, and stabilizes existing plaques on the vessel wall. In addition, sRAGE also prevents the formation of neointima prompted by vascular injuries and hence inhibits restenosis. We have developed Chinese Hamster Ovary (CHO) cell lines that stably express sRAGE, and the accompanied affinity purification strategies that produce homogenous sRAGE. Preliminary studies in animal restenosis models showed that sRAGE produced in our lab has significantly higher efficacy than reported. Current work has focused on determination of effective blocking dose of sRAGE in restenosis animal models. Assessment of molecular basis of such high efficacy is underway, and in vivo half-life and ligand binding capacity are also underway. To further develop sRAGE as an effective therapeutic product, we, in collaboration with Department of Energys Ames Laboratory, also initiated studies using mesoporous silica nanoparticle-based drug delivery system for a more effective in vivo delivery, and controlled release. We hope to develop nanoparticle delivery-release system carrying sRAGE in combination with other anti-inflammatory and anti-thrombosis drug to effectively combat vascular diseases. The reagent is currently under development, and is not available for public or commercial usage. To overcome technical hurdles for expression and detection of sRAGE, we also developed a set of expression modules that facilitate subcloning, cell-surface expression. and epitope tagging of mammalian membrane proteins. U.S. Provisional patent (No. 61/142,531) has been awarded to this invention, and NIH is currently advertising the invention. R&D Status: Pre-clinical in vitro.