Elastin Peptide-Based Fusion Proteins to Promote Skin Wound Repair

With an aging population and an increased prevalence of diabetes, there is a concomitant increase in incidence of chronic nonhealing wounds of skin. Common types of chronic wounds are diabetic foot ulcers, pressure ulcers, and venous ulcers, which require a series of expensive and complex treatment modalities. Chronic wounds typically exhibit lowered levels of chemokines and growth factors that are normally responsible for promoting cell migration and proliferation, the basic processes that are involved in tissue repair. Peptide growth factors have generally not been successful as therapeutics, with the exception of topical platelet-derived growth factor (PDGF), due to impaired responsiveness of wound cells to growth factor signals, and increased levels of proteases in the wound environment that degrade exogenously applied growth factors.<br/><br/>We have developed, using fusion protein technology, recombinant proteins comprising bioactive peptides relevant to woind healing and elastin like peptides (ELPs). ELPs are derivatives of tropoelastin and confer the ability of the protein to reversibly self-assemble into nanoparticles. In addition, the nanoparticles can be easily purified by centrifugation during manufacture of the product, thus obviating the need for expensive chromatographic methods. We have used this approach for the development of a stabilized form of stromal-derived factor-1 (SDF-1), a pro-angiogenic chemokine in wound healing, and a stabilized form of the v-domain of the receptor for advanced glycation endproducts (vRAGE). The ELP-SDF-1 and ELP-vRAGE fusion proteins exhibit bioactivities similar to that of their counterparts SDF-1 and sRAGE, respectively, in in vitro cell culture assays. However, they exhibit greater efficacy when used topically on mouse wounds. We hypothesize that the greater efficacy in vivo is due to greater stability in the wound fluid environment. Our next step is to develop other fusion proteins that can be combined together that target different cell types and processes in the wound healing cascade.