Angiotensin Analogs to Treat Wound Healing

描述（由申请人提供）： 数百万美国人患有与糖尿病溃疡、压力性溃疡、静脉淤滞性溃疡和烧伤相关的慢性伤口。在许多情况下，慢性伤口可能需要数年才能愈合，复发率很高，每年有54，000名患者需要截肢。据估计，美国约有220万患者患有对传统疗法无反应的慢性溃疡。伤口愈合市场代表了道德伤口愈合剂方面的巨大未满足需求。Maret已经表明，血管紧张素肽可以快速有效地促进伤口愈合。在我们的I期SBIR资助中，我们鉴定了一种化合物（MARskinTM）（NorLeu 3-A（1-7）），其在伤口愈合中具有上级性质。在伤口修复的不同动物模型中的体内研究中，NorLeu 3-A（1-7）上级唯一FDA批准的治疗伤口愈合的药物。这些初步研究确定了NorLeu 3-A（1-7）作为我们开发伤口愈合药物的主要化合物。在这个II期SBIR中，我们将完成支持该药物临床试验启动所需的临床前研究。具体而言，我们将在尤卡坦小型猪模型中测试NorLeu 3-A（1-7），该模型是用于确定伤口修复功效的行业标准动物模型。此外，我们将开发用于临床试验的最有效的化合物制剂，并将确定局部使用NorLeu 3-A（1-7）的药代动力学和安全性。我们还将使用DNA微阵列和蛋白质芯片技术研究NorLeu 3-A（1-7）在伤口愈合中的分子作用机制。在目标2中，我们将制定NorLeu 3-A（1-7）在伤口愈合中的临床方案，包括招募临床研究者，以便我们可以向FDA提交IND豁免，用于人体试验，为未来启动I期安全性和II期疗效试验做准备。除了NorLeu 3-A（1-7）之外，在我们的I期SBIR研究中还鉴定了6种肽，其选择性地结合AT 2受体，在体内进行了评价，并显示出是有希望的组织修复候选药物。由于AT 2受体在伤口组织中独特表达，因此这些肽可能对伤口愈合具有任何其他试剂都没有发现的高度特异性。在这个II期SBIR中，这些化合物将进行广泛的临床前测试，以确定它们是否应该作为第二代伤口愈合药物进一步开发。

DESCRIPTION (provided by applicant): Millions of Americans suffer from chronic wounds associated with diabetic ulcers, pressure ulcers, venous stasis ulcers and bums. In many cases the chronic wounds can take years to heal, have a high recurrence rate and for 54,000 patients a year, result in amputations. It is estimated that about 2.2 million patients in the United States have chronic ulcers that don't respond to conventional therapies. The wound healing market represents a large unmet need in terms of ethical wound healing agents. Maret has shown that angiotensin peptides can rapidly and effectively promote wound healing. In our phase I SBIR grant, we identified a compound (MARskinTM)(NorLeu3-A (1-7)), with superior properties in wound healing. In in vivo studies in different animal models of wound repair, NorLeu3-A (1-7) was superior to the only FDA approved drug to treat wound healing. These initial studies established NorLeu3-A (1-7) as our lead compound to develop as a wound-healing drug. In this phase II SBIR we will complete the preclinical studies needed to support the initiation of clinical trials with this drug. Specifically, we will test NorLeu3-A (1-7) in the Yucatan miniswine model, which is the industry standard animal model for establishing efficacy in wound repair. Furthermore, we will develop the most effective formulation of the compound for clinical trials, and will determine pharmacokinetics and safety of NorLeu3-A (1-7) for topical use. We will also investigate the molecular mechanisms of action of NorLeu3-A (1-7) in wound healing using DNA microarray and protein chip technologies. In Aim 2, we will develop a clinical protocol for NorLeu3-A (1-7) in wound healing, including recruitment of clinical investigators so that we can file an IND Exemption with the FDA for human testing in preparation for the initiation of Phase I safety and Phase II efficacy trials in the future. In addition to NorLeu3-A (1-7), six peptides were identified in our phase I SBIR studies that bound selectively to AT2 receptors, were evaluated in vivo and were shown to be promising tissue repair drug candidates. Because AT2 receptors are uniquely expressed in wound tissue, these peptides may have a high degree of specificity for wound healing not found with any other agents. In this phase II SBIR, these compounds will undergo extensive preclinical testing to determine whether they should be further developed as a second generation of wound healing drugs.