Transdermal Delivery of Deferoxamine to Prevent and Treat Diabetic Wounds

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DESCRIPTION (provided by applicant): New vessel growth is essential for the delivery of nutrients and maintenance of oxygen homeostasis in cutaneous tissue repair. Diabetic patients are at an increased risk for impaired tissue recovery following ischemic insult and are known to have severe deficits in wound healing. Diabetic foot ulcers represent one of the most common sequelae of diabetes-associated dysfunction in new blood vessel growth. The predictable location of these lesions and their well-described pathophysiology makes diabetic foot ulcers an ideal target for therapeutic interventions aimed at treatment and prevention through restoration of normal neovascularization. We and others have demonstrated that this dysfunction is attributable to diminished activity of the transcription factor hypoxia-inducible factor-1 alpha (HIF-11). We have previously demonstrated that systemic delivery of the small molecule deferoxamine (DFO) is suficient to stabilize HIF-11 in diabetic models, resulting in improved wound healing and decreased tissue necrosis. Using a novel transdermal patch developed in our laboratory, we have determined that targeted transdermal delivery of DFO (an FDA-approved drug) is effective to both prevent pressure ulcer formation and accelerate wound healing in preclinical models. In this proposal, we seek to assess the feasibility of employing this transdermal patch for the treatment and prevention of non- healing foot ulcers in diabetic patients. Approaches that only address the treatment of diabetic wounds fail to account for the fact that the vast majority of these complications are predictable and can potentially be prevented. Here we describe a novel, prophylactic strategy to enhance local blood vessel formation and other hypoxia-induced responses, which has the potential to significantly attenuate both the formation and progression of wound healing complications in diabetic patients. We first seek to establish the regulatory feasibility of our transdermal device for human diabetic patients (SA1). We will then conduct biostatistical analyses to confirm the feasibility of our outcome measures and begin to develop sample size calculations; this will permit us to begin building a rudimentary trial design in accordance with an eventual manual of procedures (SA2). Finally, we will begin to reach out to potential clinical collaborators in order to evaluate the logistical factors for these investigations (SA3). PUBLIC HEALTH RELEVANCE: Diabetes is a known risk factor for impaired wound healing and poor tissue recovery following an ischemic insult. Accordingly, diabetes is associated with an increased risk of vascular comorbidities including cardiovascular and peripheral vascular disease, as well as impairments in wound healing. New vessel growth is essential for the delivery of nutrients and maintenance of oxygen homeostasis in cutaneous tissue repair, and inadequate vasculogenesis is a major factor in the development of chronic wounds. These include diabetic foot ulcers, which represent one of the most common sequelae of diabetes-associated impairments in wound healing. While the attention given to preventing and treating the sequelae of type 2 diabetes has been warranted given its increasing global prevalence, type 1 diabetes remains a major cause of morbidity and mortality, especially in children. As treatment regimens for type 1 diabetes have improved, there are more adults living with this chronic disease, which translates to an increasing burden of diabetes-related complications across all age groups. Approaches that only address the treatment of diabetic wounds fail to account for the fact that the vast majority of these complications are predictable and can potentially be prevented. Here we describe a novel, prophylactic strategy to enhance local blood vessel formation and other hypoxia-induced responses, which has the potential to significantly attenuate both the formation and progression of wound healing complications in diabetic patients.