Angiotensin Analogs to Treat Wound Healing

描述(由申请人提供)： 数以百万计的美国人患有与糖尿病溃疡、压疮、静脉淤积性溃疡和烧伤有关的慢性伤口。在许多情况下，慢性伤口可能需要数年时间才能愈合，复发率很高，每年有54,000名患者会导致截肢。据估计，美国约有220万患者患有对传统疗法无效的慢性溃疡。就合乎道德的伤口治愈剂而言，伤口愈合市场代表着一个巨大的未得到满足的需求。Maret研究表明，血管紧张素肽可以快速有效地促进伤口愈合。在我们的第一阶段SBIR赠款中，我们确定了一种在伤口愈合中具有优异性能的化合物(MARskinTM)(NorLeu3-A(1-7))。在不同伤口修复动物模型的体内研究中，NorLeu3-A(1-7)优于FDA批准的唯一治疗伤口愈合的药物。这些初步研究确定NorLeu3-A(1-7)是我们开发成伤口愈合药物的先导化合物。在这个第二阶段的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。具体地说，我们将在尤卡坦迷你葡萄酒模型中测试NorLeu3-A(1-7)，这是建立伤口修复有效性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配方，并将确定局部使用的NorLeu3-A(1-7)的药代动力学和安全性。我们还将利用DNA芯片和蛋白质芯片技术研究NorLeu3-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NorLeu3-A(1-7)在伤口愈合方面的临床方案，包括招募临床研究人员，以便我们可以向FDA申请IND豁免进行人体试验，为未来启动I期安全性和II期疗效试验做准备。除NorLeu3-A(1-7)外，在我们的I期SBIR研究中还发现了6个与AT2受体选择性结合的多肽，并在体内进行了评估，表明它们是有前景的组织修复药物候选药物。由于AT2受体在伤口组织中是唯一表达的，这些多肽可能具有其他任何药物所没有的高度的伤口愈合特异性。在这一第二阶段的SBIR中，这些化合物将接受广泛的临床前测试，以确定它们是否应该进一步开发为第二代伤口愈合药物。

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.