PARS inhibitor therapy of smoke inhalation injury

烟雾吸入和烧伤可诱发炎性肺炎，并可发展为严重的呼吸衰竭。目前的治疗选择仅限于支持性措施。我们建议测试的可行性，一个革命性的抗炎方法在烟雾吸入性急性肺损伤（ALI）的管理。最近发现的炎性损伤的机制，“聚（ADP-核糖）合成酶（PARS）途径”，已经涉及炎性损伤的发病机制。由氧化剂诱导的DNA单链断裂触发，PARS催化ADP-核糖的能量消耗聚合，导致NAD耗尽，抑制糖酵解和线粒体呼吸，并最终减少细胞内高能磷酸盐。PARS活化还强烈上调促炎细胞因子、趋化因子和粘附分子的表达。PARS抑制剂的给药已被证明在炎症和血流改变的实验模型中具有保护作用，包括关节炎、中风和内毒素休克。这项拨款提案的中心目标是确定Inotek的主要PARS抑制剂PJ-34在热损伤诱导的ALI的绵羊模型中改善血流动力学、终末器官损伤和氧合。在烟雾吸入和烧伤后，绵羊将用PJ-34（3-30 mg/kg i. v.）治疗。将肺血管阻力、体循环血管阻力、心输出量和PaO 2/FiO 2比值较基线的百分比变化与未治疗对照组进行比较。在48小时时，我们将测量PJ-34对肺损伤的一系列炎症指标的影响，以评估脂质过氧化、中性粒细胞浸润、组织学和过氧亚硝酸盐形成。我们将PJ-34的功效与其血清浓度相关联，以创建药效学特征。我们预期，PJ-34将剂量依赖性地减少在该临床相关的烟雾吸入和烧伤组合模型中的肺部炎症和损伤。拟议的商业应用：烧伤和烟雾吸入引起的ALI对医疗保健市场的年度国内影响估计为> 5000万美元。全球市场（仅发达国家）是其四倍。鉴于缺乏一种特定的，安全的，方便的现有疗法，Inotek预计市场接受将迅速实现，在高水平的渗透，并与高持续的价格点（每名患者1000美元）。市场进入和成熟后的全球总销售收入估计（约FDA批准后4年）相当于2.5亿美元（每年）。

Smoke inhalation and burn injury induce an inflammatory pneumonitis that may progress to severe respiratory failure. Current treatment options are limited to supportive measures. We propose to test the feasibility of a revolutionary anti-inflammatory approach in the management of smoke inhalation induced acute lung injury (ALI). A recently discovered mechanism of inflammatory injury, the "Poly (ADP-ribose) Synthetase (PARS) Pathway", has been implicated in the pathogenesis of inflammatory injury. Triggered by oxidant-induced DNA single strand breaks, PARS catalyzes an energy-consuming polymerization of ADP- ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates. PARS activation also strongly upregulates expression of pro-inflammatory cytokines, chemokines, and adhesion molecules. The administration of PARS inhibitors has been shown to have a protective effect in experimental models of inflammation and altered blood flow, including arthritis, stroke, and endotoxic shock. The central objective of this grant proposal is to establish that Inotek's lead PARS inhibitor, PJ-34, improves hemodynamics, end-organ injury, and oxygenation in an ovine model of thermal injury induced ALI. After smoke inhalation and burn injury, sheep will be treated with PJ-34 (3-30 mg/kg i.v.). The percent change from baseline pulmonary vascular resistance, systemic vascular resistance, cardiac output, and PaO2/FiO2 ratio will be compared to untreated controls. At 48 h, we will measure the effect of PJ-34 on a comprehensive series of inflammatory indices of lung injury to assess lipid peroxidation, neutrophil infiltration, histology, and peroxynitrite formation. We will correlate the efficacy of PJ-34 with its serum concentration, in order to create a pharmacodynamic profile. We expect that PJ-34 will dose-dependently reduce lung inflammation and injury in this clinically relevant model of combined smoke inhalation and burn injury. PROPOSED COMMERCIAL APPLICATIONS: The annual domestic impact of burn injury and smoke inhalation induced ALI on the health care market is estimated at > $50 million. The worldwide market (developed countries only) is four times larger. Given the absence of a specific, safe, and convenient existing therapy, Inotek anticipates market acceptance to be achieved rapidly, at high levels of penetration, and with a high sustained price point ($1000 per patient). Estimated worldwide gross sales revenues after market entry and maturation (ca. 4 years after FDA approval) equal $250 million (annual).