Recombinant Alpha-1 Antitrypsin as a Novel Therapy for Pandemic Influenza
Abstract
FY21 PRMRP Topic Area: Respiratory Health Central Clinical Problem: Viral influenza infection is a global issue and kills many thousands of people worldwide each year. There are a number of different strains of influenza, with a range in their severity. Seasonal influenza infection is the usual type that occurs every year; particularly in the winter time. Seasonal influenza generally causes a moderate degree of respiratory inflammation and symptoms. However, it remains an important cause of death in the elderly and those subjects with underlying lung disease, such as patients with chronic lung diseases. From time to time, much more virulent strains of influenza occur, which may cause epidemics. This virulent influenza may occur when a completely new strain arises (as may arise from birds, bird flu). Over the past hundred years, there have been worldwide influenza epidemics termed pandemics. The most well-known pandemic occurred in 1918 the Spanish flu, which resulted in the death of approximately 20-50 million people. In this outbreak, a large proportion of the deaths occurred in healthy young adults. The pandemic influenza strains may cause severe inflammation in the lung, resulting in widespread damage to the lung tissue. In this circumstance, the overwhelming infection and inflammation may cause the lungs to fail and result in death. There is currently no effective anti-inflammatory therapy for the treatment of severe influenza lung infection. Influenza infection triggers a number of inflammatory immune responses in the lung that may lead to tissue damage. One potentially relevant inflammatory mechanism is the expression of an extracellular trap by the lung white cells. These traps are composed of extracellular extensions of DNA with other chemicals that kill microbes. These chemicals may potentially digest the lung. The production of extracellular traps by the white cells may be an important inflammatory pathway that damages the lung and may lead to other complications such as respiratory failure and bacterial infection. We believe that two widely available drugs, alpha-1 antitrypsin (AAT) and deoxyribonuclease 1 (DNase 1 or drug name dornase alfa) can be repurposed to prevent lung damage from extracellular traps. We have established a comprehensive research program to prove this hypothesis and have compelling preliminary experimental results. Innovation: We have developed a unique level of expertise to study how influenza infection induces extracellular trap expression in the lung with consequent severe inflammation and lung damage. The idea that virulent influenza causes excessive activation of extracellular traps in young people leading to severe lung disease is novel. There is no effective anti-inflammatory therapy available for the treatment of severe influenza infection. We believe that our work will result in new therapies for this globally devastating condition. To facilitate this, we have developed a unique form of AAT, which has significant advantages over the currently available form from human blood donors. In addition, our idea of combining AAT and DNase 1 to treat influenza infection is novel. Ultimate Applicability and Impact: Pandemic influenza remains a global threat. We believe that this work may lead to the repurposing of a widely used and safe medications as new anti-inflammatory agents for the treatment of severe influenza. It will provide a rationale to initiate clinical trials to test these therapies in human subjects. The findings are likely to be particularly relevant for healthy young adults such as defense force personnel.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210254
Entities
People
- Paul King
Organizations
- Monash University
- United States Army