Inhaled aerosols for prevention and treatment of respiratory infections

描述（由申请人提供）： 该研究的长期目标是表征和开发下一代气雾剂制剂，用于治疗和抗传染各种呼吸道传染病，比目前的制剂更有效和用户友好。具体来说，我们的目标是确定一种用于治疗和抗流感（NIAID C类优先病原体）的主要治疗药物。呼吸道感染是发达国家和发展中国家发病率和死亡率的重要来源。预防或治疗感染的常规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，这共同阻碍了它们的部署和效用。Pulmatrix正在开发一种新的气雾剂疗法，含有简单的阳离子（例如，钙），其可以提供用于治疗广泛的病毒和细菌呼吸道感染的广谱、大量使用的方法。该方法的原理是基于通过阳离子气溶胶调节呼吸道上皮的气道衬里液（ALF）的表面流变学性质和刺激对病毒和细菌病原体的先天性和适应性免疫应答。这些新型气溶胶已被证明：减少人类呼出的生物气溶胶;阻止猪流感的传播并治疗猪流感;治疗鼠细菌性肺炎;并改变粘液模拟物的流变性质，这表明可以开发另外的气雾剂疗法来治疗和控制细菌和病毒呼吸道感染，反过来，盐气溶胶的治疗和抗传染作用通过改变ALF的流变学性质而发生，导致ALF的生物气溶胶产生减少，和/或或者通过改变感染的进程具体目标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和气道衬里液中生物气溶胶的形成; 2.通过测试细菌和病毒穿过暴露于盐气溶胶的粘液模拟物的能力，以及盐气溶胶是否降低细胞培养模型中甲型流感的感染性，检查盐气溶胶对病原体感染性的影响; 3.在猪流感感染模型中，在体内确定生物气溶胶产生减少对空气传播和呼吸道感染的影响。项目里程碑：确定用于治疗流感和抑制呼出生物气溶胶产生的铅盐气雾剂制剂，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。这些感染占全球疾病总负担的6%以上，比艾滋病毒/艾滋病、疟疾和腹泻等疾病的负担更高。因此，非常需要用于对抗这些感染的简单、广谱的预防/治疗策略，例如本文提出的作为盐的气雾剂制剂。

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.