Transdermal Delivery of Deferoxamine to Prevent and Treat Diabetic Wounds

描述（由申请方提供）：新血管生长对于皮肤组织修复中营养物质的输送和氧稳态的维持至关重要。糖尿病患者在缺血性损伤后组织恢复受损的风险增加，并且已知在伤口愈合方面具有严重缺陷。糖尿病足溃疡代表糖尿病相关的新血管生长功能障碍的最常见后遗症之一。这些病变的可预测位置及其充分描述的病理生理学使糖尿病足溃疡成为旨在通过恢复正常新血管形成进行治疗和预防的治疗干预的理想靶点。我们和其他人已经证明，这种功能障碍是由于转录因子缺氧诱导因子-1 α（HIF-11）的活性降低。我们以前已经证明，全身递送小分子去铁胺（DFO）足以稳定糖尿病模型中的HIF-11，从而改善伤口愈合和减少组织坏死。使用我们实验室开发的一种新型透皮贴剂，我们已经确定DFO（一种FDA批准的药物）的靶向透皮给药在临床前模型中可有效预防压疮形成并加速伤口愈合。在本提案中，我们试图评估采用这种透皮贴剂治疗和预防糖尿病患者不愈合足部溃疡的可行性。仅解决糖尿病伤口治疗的方法未能解释绝大多数这些并发症是可预测的并且可以潜在地预防的事实。在这里，我们描述了一种新的，预防性的策略，以提高局部血管形成和其他缺氧诱导的反应，这有可能显着减弱糖尿病患者伤口愈合并发症的形成和进展。我们首先寻求建立我们的经皮装置用于人类糖尿病患者（SA 1）的监管可行性。然后，我们将进行生物统计学分析，以确认我们的结局指标的可行性，并开始开发样本量计算;这将使我们能够开始根据最终的程序手册（SA 2）构建基本的试验设计。最后，我们将开始接触潜在的临床合作者，以评价这些研究的后勤因素（SA 3）。 公共卫生相关性：糖尿病是缺血性损伤后伤口愈合受损和组织恢复不良的已知风险因素。因此，糖尿病与包括心血管和外周血管疾病在内的血管合并症以及伤口愈合障碍的风险增加相关。新血管生长对于皮肤组织修复中营养物质的输送和氧稳态的维持是必不可少的，并且血管生成不足是慢性伤口发展的主要因素。这些包括糖尿病足溃疡，其代表糖尿病相关伤口愈合损伤的最常见后遗症之一。虽然由于2型糖尿病在全球的流行率不断增加，因此有必要对预防和治疗其后遗症给予关注，但1型糖尿病仍然是发病率和死亡率的主要原因，特别是在儿童中。随着1型糖尿病治疗方案的改善，越来越多的成年人患有这种慢性疾病，这意味着所有年龄组的糖尿病相关并发症的负担越来越大。仅解决糖尿病伤口治疗的方法未能解释绝大多数这些并发症是可预测的并且可以潜在地预防的事实。在这里，我们描述了一种新的，预防性的策略，以提高局部血管形成和其他缺氧诱导的反应，这有可能显着减弱糖尿病患者伤口愈合并发症的形成和进展。

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.