Novel peptide to inhibit burn injury progression

描述（由申请人提供）：烧伤是人类已知的最常见和最具破坏性的伤害之一。在美国，每年约有50万烧伤患者到急诊室就诊。在每年40，000名住院患者中，每年有25，000名烧伤患者入住专门的烧伤中心。烧伤的总死亡率约为5%，每年报告的死亡人数接近4000人。此外，烧伤给人类、社会和经济造成的负担相当大，估计每年的直接费用超过20亿美元，间接费用更大。该提案的资助将是满足严重烧伤患者护理未满足需求的一步，即预防烧伤进展的治疗。这种疗法有可能减少疼痛和痛苦，最大限度地减少切除和移植的需要，降低感染率，减少住院治疗，减少费用并减少烧伤受害者的疤痕。在大鼠热梳模型中，在烧伤后1和24小时静脉内给予纤连蛋白衍生的14个氨基酸肽（P12），已经获得了这种治疗的原理证明。在该模型中，使用最佳剂量的P12几乎完全抑制了烧伤进展。在开始这种新疗法的临床试验之前，需要对这一发现进行大型动物证实。因此，我们建议在经验证的猪热梳模型（AIM 1）中确认大鼠研究并优化治疗方案。猪模型通常被认为是研究人类皮肤损伤的最佳模型，因为猪皮肤与人类皮肤最相似。此外，我们建议在体内和体外研究，以更好地阐明P12的作用机制（AIM 2和3，分别）。基于成人皮肤成纤维细胞（AHDF）的初步结果，我们假设P12保护细胞免于氧化和细胞因子应激诱导的凋亡或坏死性死亡。将对来自AIM 1中概述的猪实验的组织标本进行体内研究（AIM 2），以解决该假设;然而，体外研究将利用人皮肤细胞弥合其他动物种属与人之间的差距。AIM 1 - 3和AIM 4的P12稳定性和毒代动力学研究的结果对于I期和II期临床试验（AIM 4）的设计至关重要。PHS 398/2590（Rev. 11/07）第1页

DESCRIPTION (provided by applicant): Burns are one of the most common and devastating injuries known to mankind. Each year in the US approximately 500,000 patients with burns present to emergency departments. Of 40,000 annual hospitalizations, 25,000 burn victims are admitted to specialized burn centers annually. The overall mortality from burns is around 5%, with nearly 4000 deaths reported yearly. In addition, the human, social and economic burden of burns is considerable with an estimated annual expenditure of more than $2 billion direct costs and much greater indirect costs. Funding of this proposal would be a step toward fulfilling an unmet need in the care of patients with severe burns, i.e. treatment to prevent burn injury progression. Such therapy would potentially reduce pain and suffering, minimize need for excision and grafting, decrease infection rate, reduce hospitalization, diminish cost and lessen scarring of burn victims. Proof of principle for such a therapy has been obtained with a fibronectin-derived 14 amino acid peptide (P12) administered intravenously 1 and 24 hr after burn injury in a rat hot comb model. Almost complete inhibition of burn injury progression was achieved in this model with optimal doses of P12. Large animal confirmation of this finding is required prior to the initiation of clinical trials with this novel therapy. Therefore, we propose to confirm the rat studies and optimize the treatment protocol in a validated porcine hot comb model (AIM 1). Porcine models are generally recognized as best for studying injuries to human skin since porcine skin most closely resembles that of humans. In addition, we propose in vivo and in vitro studies to better elucidate P12 mechanism of action (AIMs 2 and 3, respectively). Based on preliminary results with adult human dermal fibroblasts (AHDF), we hypothesize that P12 protects cells from apoptotic or necrotic death induced by oxidative and cytokine stress. In vivo studies to address this hypothesis (AIM 2) will be performed on tissue specimens from the porcine experiments outlined in AIM 1; however, the in vitro studies will utilize human skin cells to bridge the gap from other animal species to human. Results from AIMs 1 - 3 and P12 stability and toxicokinetic studies from AIM 4 are critical for the design of Phase I and II clinical trials (AIM 4). PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page