STTR Phase I: Polymer Surfactant Therapy for Acute Respiratory Distress Syndrome (COVID-19)

这个小企业技术转让(STTR)第一阶段项目的更广泛的影响/商业潜力将是开发一种首创的治疗急性呼吸窘迫综合征(ARDS)以及可能以高死亡率、发病率和住院时间为特征的其他严重呼吸系统疾病的治疗方法。急性呼吸窘迫综合征导致肺表面活性物质失活，而表面活性物质负责保持肺结构的膨胀和干燥。这会导致血液氧合不足和多器官衰竭，而不进行有创性机械通气。据信，急性呼吸窘迫综合征占全球重症监护病房床位的7%，可由许多根本原因引起，包括直接肺损伤(即细菌性/病毒性肺炎)和间接肺损伤(即创伤)。就疫情而言，目前的数据表明，14%的新冠肺炎病例需要住院治疗。在这些患者中，每3人中就有1人会患上ARDS，使他们的存活率降至60%。在正常情况下，全球有300万例ARDS病例(22万美国)是高度资源密集型的(平均82000美元的治疗费用)，这给患者和医疗保健系统带来了相当大的经济负担。治疗性治疗将减少患者死亡和慢性并发症的频率。拟议的项目将开发一种不同的方法，通过合成聚合物肺表面活性物质(PLS)技术治疗ARDS。这种偏最小二乘技术克服了以前尝试的疗法的缺点，因为它被设计成在人体内安全使用，高度表面活性(较低的表面张力)，水溶性(在可注射水悬浮液中制备)，以及抵抗蛋白质失活。悬浮在溶液中的聚乳酸均匀地分布在机械通气患者的肺部。当PLS到达肺泡时，它会形成一层透气的胶束单分子层，模拟人类肺表面活性物质的功能，而不会被灭活。这样做会使肺泡重新充气，同时减少液体堆积和炎症，从而恢复血液的氧合。该项目的具体目标#1建立在有希望的最低限度安全性/有效性概念验证数据的基础上，将优化因不同根本原因(感染和酸吸入)而导致ARDS的小鼠的给药参数。具体目标#2将使用碘标记的最小二乘法生成从分娩到治疗后几天的小鼠体内的分布和清除数据。这些数据将用于优化关键交付和最小二乘法参数，以确保在几天内保持最大效率。该奖项反映了NSF的法定使命，并已通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Small Business Technology Transfer (STTR) Phase I project will be to develop a first-in-kind therapeutic for treatment of Acute Respiratory Distress Syndrome (ARDS) as well as potentially other severe respiratory conditions that are characterized by high rates of mortality, morbidity, and hospitalization time. ARDS causes deactivation of the lungs’ surfactant, which is responsible for keeping the lung structure inflated and dry. This causes inadequate blood oxygenation and mutli-organ failure without invasive mechanical ventilation. ARDS is believed to account for 7% of the world’s ICU beds and can be caused by many root causes, including both direct lung injuries (i.e. bacterial/viral pneumonia) and indirect lung injuries (i.e. trauma). In the case of the pandemic, current data suggests that 14% of COVID-19 cases require hospitalization. Of these patients, 1 in 3 will develop ARDS, reducing their chance of survival to 60%. In a normal year there are 3 million ARDS cases globally (220k US) that are highly resource intensive (avg. $82k treatment cost), which presents a considerable financial burden on patients and healthcare systems. A therapeutic treatment would reduce patient deaths and frequency of chronic complications.The proposed project will develop a different approach to ARDS treatment via a synthetic Polymer Lung Surfactant (PLS) technology. This PLS technology overcomes shortcomings of previously attempted therapies as it is engineered to be safely used in the body, highly surface-active (lower surface tension), water-soluble (prepared in injectable aqueous suspension), and resistant to protein deactivation. Suspended in solution, PLS is evenly distributed in the lungs of mechanically ventilated patients. When PLS reaches the alveoli, it forms a gas-permeable micelle monolayer that mimics the function of human lung surfactant without being deactivated. Doing so re-inflates the alveoli while reducing fluid accumulation and inflammation so that blood oxygenation can be restored. Building upon promising PLS safety/efficacy proof-of-concept data, specific aim #1 of this project will optimize delivery parameters in mice that have been induced with ARDS by differing root causes (infection vs. acid-aspiration). Specific aim #2 will use iodine-labeled PLS to generate distribution and clearance data in mice from delivery to several days post-treatment. This data will be used to optimize key delivery and PLS parameters to ensure that maximum efficacy is sustained for several days.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.