Chelating the valley of death: Deferoxamine’s path from bench to wound clinic

Abstract

There is undisputable benefit in translating basic science research concretely into clinical practice, and yet, the vast majority of therapies and treatments fail to achieve approval. The rift between basic research and approved treatment continues to grow, and in cases where a drug is granted approval, the average time from initiation of human trials to regulatory marketing authorization spans almost a decade. Albeit with these hurdles, recent research with deferoxamine (DFO) bodes significant promise as a potential treatment for chronic, radiation-induced soft tissue injury. DFO was originally approved by the Food and Drug Administration (FDA) in 1968 for the treatment of iron overload. However, investigators more recently have posited that its angiogenic and antioxidant properties could be beneficial in treating the hypovascular and reactive-oxygen species-rich tissues seen in chronic wounds and radiation-induced fibrosis (RIF). Small animal experiments of various chronic wound and RIF models confirmed that treatment with DFO improved blood flow and collagen ultrastructure. With a well-established safety profile, and now a strong foundation of basic scientific research that supports its potential use in chronic wounds and RIF, we believe that the next steps required for DFO to achieve FDA marketing approval will include large animal studies and, if those prove successful, human clinical trials. Though these milestones remain, the extensive research thus far leaves hope for DFO to bridge the gap between bench and wound clinic in the near future.

Deferoxamine as adjunct therapeutics for tuberculosis

“…19 Additionally, DFO is an FDA-approved drug with pro-inflammatory properties and is utilized in humans for conditions like hemochromatosis. 23 Here, we have demonstrated the role of DFO as an adjunct therapeutic in reducing the Mtb burden by limiting iron availability in the C57BL/6 mice. Although, male mice were used in this study, iron chelation in both sexes will limit Mtb growth.…”

A nutritional immunity blockade controls extracellular bacterial replication inLegionella pneumophilainfections

“…Because iron was critical for Lp extracellular growth in the presence of serum, we investigated if iron is required of Lp growth under SF conditions by treating cells with deferoxamine (DFO) – a non-toxic iron chelator that is clinically approved and effective for treatment of iron-overload pathological conditions. 101 Treatment with 25µM DFO restricted Lp extracellular replication in monocyte infections as measured by a bioluminescence growth assay (Fig. 6a) and live-cell imaging (Fig.…”

Cellular therapeutics and immunotherapies in wound healing – on the pulse of time?

“…And across the three diabetic murine models, iridium treatment increased wound closure by up to 25% after 4 d. These changes were accompanied by increased skin thickness, collagen deposition, and importantly, neovascularization. Finally, Parker et al [ 31 ] provide a narrative review that further explores the successes of DFO in pre-clinical models of wound healing and how those results may promote human trials to evaluate its effectiveness in clinical practice.…”

“…Chelation of iron then indirectly inhibits HIF-1-PHD, increasing the abundance of HIF-1 which leads to increased vascular endothelial growth factor (VEGF) expression Pre-clinical murine model DFO is FDA-approved with indications for iron overload and is not currently indicated for the treatment of chronic wounds The study was only pre-clinical and had a small sample size. Moreover, effect sizes were statistically significant but relatively small [ 30 , 31 ] Cyclometalated iridium (III) metal complex 1a Cyclometalated iridium (III) metal complex 1a functions as a stabilizer of HIF-1α. It does so by disrupting the von Hippel-Lindau-HIF-1α protein interaction, allowing for the accumulation of HIF-1 in cellulose.…”