Plasma Gelsolin as Immunotherapeutic for Antibiotic-Resistant Pneumonia

摘要 问题：抗生素耐药性是对公共健康的一个严重且日益严重的威胁。RFA 这促使我们的建议鼓励“调节宿主免疫反应以对抗感染” 和/或减少疾病病理。“建议的解决方案：我们专注于一个特定的 候选免疫调节剂，血浆明胶蛋白(PGSN)，将使服用抗生素的患者受益- 耐药细菌性肺炎(ARP)的三种不同机制：1)巨噬细胞增强 细菌杀灭；2)清除肺损伤释放的细胞外肌动蛋白(抑制 细菌清除)；以及3)结合/抑制过量的促炎介质。减少 血液中的pGSN预测危重患者的不良结局，并在动物模型中恢复 从其他致命的伤害中存活下来。这导致了已经完成的、广泛的安全 以及对pGSN的毒性评价，作为其他临床问题的可能治疗方法。这 基础工作为该项目的主要目标提供了一个良好的开端：评估和优化 血浆明胶蛋白(PGSN)作为广谱免疫调节剂的应用 抗生素耐药细菌性肺炎的治疗。计划：目标1和目标2将 测试pGSN以改善原发和继发ARP小鼠模型的结果(Strep。PN， 耐甲氧西林金黄色葡萄球菌和假单胞菌)。我们将测试感染后的疗效，单独或与 次优抗生素，分析药物水平、炎症和病理参数 优化的方案，并比较全身和气雾剂输送路线。目标3将开发一种 用于人体研究的临床试验酶联免疫吸附试验。产品开发工作将解决 完成后加快临床测试所需的配方、安全性和监管问题。 意义和影响：pGSN是一种新的、针对宿主的治疗方法，已经 通过了临床使用的许多安全和监管障碍。我们预计这个项目将 建立其对多种病原体引起的感染的效用，并加速将其转化为 该诊所针对日益严重的抗药性肺炎问题。

Abstract The Problem: Antibiotic resistance is a serious and increasing threat to public health. The RFA that prompts our proposal encourage “Modulation of host immune response to combat infection and/or reduce disease pathology.” The Proposed Solution: We focus on one specific candidate immunomodulator, plasma gelsolin (pGSN) which will benefit patients with antibiotic- resistant bacterial pneumonias (ARPs) by three distinct mechanisms: 1) enhanced macrophage bacterial killing; 2) clearance of extracellular actin released by lung injury (which inhibits bacterial clearance); and 3) binding/dampening excess pro-inflammatory mediators. Diminished pGSN in blood predicts poor outcome in critically ill patients, and restoration in animal models allows survival from otherwise fatal injuries. This has led to already completed, extensive safety and toxicity evaluation of pGSN as a possible therapeutic for other clinical problems. This groundwork provides a strong start for the main goal of this project: to assess and optimize use of plasma gelsolin (pGSN) as a broad-spectrum immunomodulator to improve treatment of antibiotic-resistant bacterial pneumonias ARPs. The Plan: Aims 1 and 2 will test pGSN for improved outcome in primary and secondary ARP mouse models (Strep. pn, MRSA, and Pseudomonas). We will test post-infection efficacy, alone or in combination with suboptimal antibiotics, analyze drug levels, inflammatory and pathologic parameters in optimized protocols, and compare systemic vs. aerosol delivery routes. Aim 3 will develop a clinical testing ELISA assay for use in human studies. Product development efforts will address formulation, safety and regulatory issues needed to expedite clinical testing upon completion. The Significance & Impact: pGSN is a novel, host-targeted therapeutic that has already passed many safety and regulatory hurdles for clinical use. We expect that this project will establish its utility for infections caused by multiple pathogens, and expedite its translation into the clinic for the growing problem of antibiotic –resistant pneumonia.