Plasma Gelsolin as Immunotherapeutic for Antibiotic-Resistant Pneumonia

摘要 问题：抗生素耐药性是对公共卫生的严重和日益严重的威胁。外地住房准备金 这促使我们建议鼓励“调节宿主免疫反应以对抗感染 和/或减少疾病病理学。”建议的解决方案：我们专注于一个特定的 候选免疫调节剂，血浆凝溶胶蛋白（pGSN），这将有利于患者与抗生素- 耐药细菌性肺炎（ARPs）通过三种不同的机制：1）增强巨噬细胞 细菌杀伤; 2）清除由肺损伤释放的细胞外肌动蛋白（其抑制 细菌清除）;和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 使其免于致命伤害。这导致了已经完成的，广泛的安全 以及pGSN作为其他临床问题的可能治疗剂的毒性评价。这 基础工作为该项目的主要目标提供了一个强有力的开端：评估和优化 血浆凝溶胶蛋白（pGSN）作为广谱免疫调节剂以改善 治疗耐药性细菌性肺炎ARPs。计划：目标1和2将 测试pGSN在原发性和继发性阿普小鼠模型中改善的结果（Strep. pn， MRSA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， 优化方案，并比较全身与气雾剂递送途径。Aim 3将开发一个 临床试验用于人体研究的ELISA测定。产品开发工作将解决 在完成后加快临床试验所需的制剂、安全性和监管问题。 意义和影响：pGSN是一种新型的宿主靶向治疗药物， 通过了临床使用的许多安全性和监管障碍。我们预计，该项目将 建立其对多种病原体引起的感染的效用，并加快其转化为 抗生素耐药性肺炎问题日益严重的诊所。

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.