Inhaled aerosols for prevention and treatment of respiratory infections

描述(由申请人提供)： 这项研究的长期目标是确定和开发新一代气雾剂配方，用于治疗和抗多种呼吸道传染病，比目前的配方更有效，用户更友好。具体地说，我们的目标是确定一种治疗和抗流感传染的先导疗法(NIAID C类优先病原体)。背景在发达国家和发展中国家，呼吸道感染是发病率和死亡率的重要来源。预防或治疗感染的传统方法受到病原体特异性(“一种细菌一种药物”)和新出现的耐药性的限制，这些共同阻碍了它们的部署和使用。PulMatrix正在开发一种含有简单阳离子(例如钙)的新型气雾剂疗法，该疗法可能提供一种广谱、大规模使用的方法，用于治疗各种病毒和细菌呼吸道感染。这种方法的原理是基于调节呼吸道上皮内衬液(ALF)的表面流变性，并通过阳离子气雾剂刺激对病毒和细菌病原体的天然和获得性免疫反应。这些新型气雾剂已被证明可以减少人类呼出的生物气雾剂；阻止和治疗猪流感的传播；治疗小鼠细菌性肺炎；以及改变粘液模拟物的流变性，这表明可以开发更多的气雾剂疗法来治疗和遏制细菌和病毒呼吸道感染，这反过来可能导致呼吸道感染的广泛治疗假说治疗和盐气雾剂的抗传染作用是通过改变ALF的流变性导致ALF产生的生物气雾剂减少和/或通过改变感染过程来实现的。具体目标1.使用体外模拟咳嗽系统和界面应力流变仪，确定盐气溶胶对流变学的影响以及从呼吸道衬里液体中形成生物气溶胶的影响；2.通过测试暴露在盐气溶胶中的细菌和病毒的粘液模拟物的能力，以及在细胞培养模型中盐气溶胶是否降低甲型流感的传染性，来检测盐气溶胶对病原体传染性的影响；3.在猪的流感感染模型中，在体内确定生物气溶胶产量减少对空气传播和呼吸道感染的影响。项目里程碑：确定一种用于治疗流感和抑制呼出生物气雾剂产生的铅盐气雾剂配方，以推进临床前安全性研究和其他临床前感染模型。相关性(见说明)：急性下呼吸道感染是发病率和死亡率的重要来源。这些感染占全世界疾病总负担的6%以上，比艾滋病毒/艾滋病、疟疾和腹泻病等疾病的负担更高。因此，迫切需要简单、广谱的预防/治疗策略来对抗这些感染，例如本文提出的盐雾剂制剂。

DESCRIPTION (provided by applicant): The long term aims of the study are to characterize and develop next generation aerosol formulations for the treatment and anti-contagion of a wide range of respiratory infectious diseases, that are more efficacious and user friendly than current formulations. Specifically we aim to identify a lead therapeutic for the treatment and anti-contagion of Influenza (NIAID Category C Priority Pathogen). Background Respiratory infections are a significant source of morbidity and mortality in the developed and developing world. Conventional approaches to preventing or treating infections are limited by pathogen specificity ("one bug one drug") and emerging resistance, which collectively hinder their deployment and utility. Pulmatrix is developing a novel aerosol therapy, containing simple cations (e.g., calcium), that may provide a broad spectrum, mass use approach for the treatment of a wide range of viral and bacterial respiratory infections. The principle of this approach is based on modulation of the surface rheological properties of the airway lining fluid (ALF) of the respiratory epithelium and stimulation of the innate and adaptive immunological responses to both viral and bacterial pathogens, by cationic aerosols. These novel aerosols have been shown to: reduce exhaled bioaerosols in humans; arrest transmission of and treat porcine influenza; treat murine bacterial pneumonia; and alter the rheological properties of mucus mimetics, suggesting that additional aerosol therapies may be developed to treat and contain both bacterial and viral respiratory infections which, in turn, may lead to a broad spectrum treatment for respiratory infections Hypothesis Treatment and anti-contagion effects of salt aerosols occur by alteration of the rheological properties of the ALF leading to reduced bioaerosol production from the ALF and/or by altering the course of infection. Specific Aims 1. Define the effect of salt aerosols on rheology and the formation of bioaerosols from airway lining fluid using an in vitro simulated cough system and interfacial stress rheometry; 2. Examine the effect of salt aerosols on pathogen infectivity by testing the ability of bacteria and viruses to cross mucus mimetics that have been exposed to salt aerosols and whether salt aerosols reduce the infectivity of Influenza A in cell culture models; 3. Determine, in vivo, the effect of decreased bioaerosol production on airborne transmission and respiratory infection, in a porcine model of Influenza infection. Project Milestone: To identify a lead salt aerosol formulation for the treatment of influenza and for the suppression of exhaled bioaerosol production to be advanced into preclinical safety studies and additional preclinical models of infection. RELEVANCE (See instructions): Acute lower respiratory infections are a significant source of morbidity and mortality. These infections represent more than 6% of the total burden of disease worldwide, a higher burden than diseases such as HIV/AIDS, malaria, and diarrheal diseases. Therefore simple, broad spectrum, prophylactic/therapeutic strategies for combating these infections, such as salt aerosol formulations proposed herein are highly needed.