Restoration of Pulmonary Barrier Function in SARS-CoV-2-Associated Acute Respiratory Distress Syndrome
Abstract
Over 3,000,000 cases of coronavirus disease (COVID-19) have been reported worldwide in less than 6 months. By current estimates, 20% of these patients will advance to severe disease requiring hospitalization. In the U.S., in only 4 months (January 1-April 30), over 130,000 patients have been admitted to hospitals for COVID-19. Each of these patients, due to the lung injury caused by the SARS-CoV-2 virus (virus causing COVID-19), is at high risk of developing acute respiratory distress syndrome (ARDS). Those over 65 and with preexisting conditions are at particularly high risk for severe disease that progresses to ARDS, encompassing over 10 million U.S. Veterans. ARDS results from the destruction of the lung’s barriers that separate inspired air from fluid-filled tissues, leading to fluid accumulation, widespread immune cell influx into the lungs, and low blood oxygen levels. Of the 60,000 SARS-CoV-2-positive deaths reported in the U.S., the vast majority of these patients died due to ARDS. Once COVID-19 progresses to ARDS, the only treatment options are invasive critical care procedures including mechanical ventilation and extracorporeal membrane oxygenation (ECMO). ARDS mortality remains ~40% despite the availability of state-of-the-art critical care medicine. For patients that do recover from ARDS, poor pulmonary function and neurocognitive deficits are often lifelong complications. Compounding the dismal mortality associated with ARDS, the use of mechanical ventilation is limited by the availability of ICU beds, specialized ventilator equipment, and health care workers trained to use them. There are currently no FDA-approved therapeutics for SARS-CoV-2-associated lung damage. There is significant therapeutic potential in directly targeting the lung barrier function of COVID-19 patients to reduce lung injury, prevent disease progression, and improve survival. The transmembrane protein Connexin43 (Cx43) has well-defined roles in inflammation, tissue regeneration, and scarring. FirstString Research has bioengineered a cell-permeable peptide therapeutic, termed aCT1, that modulates Cx43 signaling to strengthen intercellular junctions, dampen inflammation, and promote an effective response to tissue injury. FirstString has formulated aCT1 into an IND-approved (#74836) topical gel (Granexin) that is currently in late-stage clinical trials for cutaneous radiation injury, cutaneous scarring, and thermal burns. Across numerous preclinical studies and six clinical trials in several injury indications, aCT1’s ability to stabilize intercellular junctions has been proven to reduce inflammation and promote an effective response to tissue injury. aCT1 would represent the first therapeutic product for COVID-19 targeting the molecular and cellular mechanisms of SARS-CoV-2-induced lung injury and ARDS, promoting barrier function integrity and limiting inflammation to prevent and treat complications of COVID-19. Treatment of COVID-19 patients with aerosolized aCT1 is expected to preserve pulmonary barrier integrity and dampen inflammation in SARS-CoV-2-infected lungs and mitigate development of ARDS in COVID-19 patients, thus lessening the need for resource intensive mechanical ventilation and dramatically improving survival. Existing IND-enabling preclinical and clinical safety data for aCT1 enable a rapid path to its clinical use in COVID-19 patients, including military Service members and Veterans. The proposed research project aims to evaluate efficacy of aerosolized aCT1 in preventing and treating SARS-CoV-2-associated lung injury and ARDS, in direct response to the following FY20 PRMRP Topic Areas: “Development of improved methods for assessing and treating lung injury due to coronaviruses, particularly COVID-19;” “Novel and/or innovative detection technologies or therapeutics to reduce the incidence and/or severity of ARDS and/or other lung injury secondary to coronaviruses, particularly COVID-19;” and “Pharmaco
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110158
Entities
People
- Meghan Bowler
Organizations
- FirstString Research (United States)
- United States Army