Transdermal Delivery of Deferoxamine to Prevent and Treat Diabetic Wounds

描述(申请人提供)：在皮肤组织修复中，新血管的生长对于营养物质的输送和维持氧平衡是必不可少的。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存在严重缺陷。糖尿病足溃疡是糖尿病相关新血管生长功能障碍最常见的后遗症之一。这些病变的可预测位置及其描述的病理生理学使糖尿病足溃疡成为治疗干预的理想靶点，旨在通过恢复正常的新生血管来治疗和预防。我们和其他人已经证明，这种功能障碍是由于转录因子低氧诱导因子-1α(HIF-11)活性降低所致。我们先前已经证明，全身注射小分子去铁胺(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。利用我们实验室开发的一种新的透皮贴剂，我们已经确定，在临床前模型中，靶向透皮传递DFO(一种FDA批准的药物)在防止压疮形成和促进伤口愈合方面都是有效的。在这项建议中，我们试图评估使用这种透皮贴片治疗和预防糖尿病患者无法愈合的足部溃疡的可行性。只处理糖尿病伤口治疗的方法没有考虑到这样一个事实，即这些并发症中的绝大多数是可以预测的，并且有可能被预防。在这里，我们描述了一种新的预防性策略，以增强局部血管形成和其他低氧诱导的反应，该策略具有显著减轻糖尿病患者伤口愈合并发症的形成和进展的潜力。我们首先寻求建立我们的用于人类糖尿病患者的透皮装置(SA1)的监管可行性。然后，我们将进行生物统计分析，以确认我们的结果衡量标准的可行性，并开始进行样本量计算；这将使我们能够根据最终的程序手册(SA2)开始建立初步的试验设计。最后，我们将开始接触潜在的临床合作者，以评估这些研究的后勤因素(SA3)。 公共卫生相关性：糖尿病是一种已知的危险因素，会导致缺血性损伤后创面愈合受损和组织恢复不良。因此，糖尿病与血管合并症的风险增加有关，包括心血管和外周血管疾病，以及伤口愈合的损害。在皮肤组织修复中，新生血管的生长对于营养物质的输送和维持氧平衡是必不可少的，而血管生成不足是慢性创面发展的主要因素。其中包括糖尿病足溃疡，这是糖尿病相关伤口愈合损害的最常见后遗症之一。尽管鉴于2型糖尿病的全球患病率不断上升，预防和治疗2型糖尿病的后遗症是必要的，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，有更多的成年人患有这种慢性疾病，这意味着所有年龄段的糖尿病相关并发症的负担都在增加。只处理糖尿病伤口治疗的方法没有考虑到这样一个事实，即这些并发症中的绝大多数是可以预测的，并且有可能被预防。在这里，我们描述了一种新的预防性策略，以增强局部血管形成和其他低氧诱导的反应，该策略具有显著减轻糖尿病患者伤口愈合并发症的形成和进展的潜力。

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.