The immune system deteriorates with age, making older people often more severely ill and have higher mortality rates after contracting COVID-19. But to date, no clinically available drug has addressed this key risk factor.
Recently, in a new study, researchers from research institutions such as the University of Iowa in the United States found that an oral drug that can reverse multiple aspects of immune aging - BGE-175 (asapiprant) - can effectively prevent the death of a mouse model of COVID-19, suggesting that the drug may be used to protect the elderly patients who are most at risk in the COVID-19 pandemic. The findings were published online on March 21, 2022 in the journal Nature under the title "Eicosanoid signaling blockade protects middle-aged mice from severe COVID-19."
In the new study, 90 percent of mice treated with BGE-175 (asapiprant) survived, while all untreated control mice died. BGE-175 treatment began two days after infection, and the mice were already developing symptoms.
The mouse model used in this study closely reflects the pathological progression of human COVID-19. The diseases caused by the strain-adapted strains constructed by these authors have many of the characteristics of human COVID-19: pulmonary balloon effusion, extensive infiltration of immune cells into lung tissue, and high levels of pro-inflammatory cytokines.
BGE-175 is currently in Phase 2 clinical trials to test whether it can prevent disease progression and death in elderly patients hospitalized for COVID-19. BGE-175 was clinically developed by BioAge Laboratories.
Co-author Dr Kristen Fortney, CEO of BioAge Laboratories, said, "The COVID-19 pandemic has devastated older populations around the world. Promising preclinical data in this paper show that in a convincing model of human COVID-19, BGE-175 almost completely protects elderly mice from death. By reversing the decline of key age-related immune mechanisms, BGE-175 may enable older patients to fight the disease more effectively. ”
Reverse immune aging through a dual mechanism
As we age, the biochemical pathways involved in the signaling molecule PGD2 become more active, impairing immunity in two main ways. First, the antigen-presenting cells of dendritic cells are less efficient at migrating, slowing down the adaptive T cell response and antibody response. Second, white blood cells more aggressively infiltrate infected tissues, leading to destructive inflammation. As a result, the older immune system is more slow to respond to new infections and is more likely to overreact once it does.
BGE-175 inhibits this pathway by blocking the interaction between PGD2 and its receptor, a protein called DP1. BioAge Labs' AI-based drug discovery platform identifies the PGD2-DP1 pathway as a key target for immune aging. In the new study, BGE-175 increased the migration of dendritic cells from the lungs to the lymph nodes, lowered neutrophil levels in lung tissue, and greatly improved overall survival. From the point of view of the activity of the PGD2 pathway, this drug restores the immune system to a more youthful state.
As with these mice treated with this drug, mice that were genetically modified to be unable to synthesize PGD2 or lacked DP1 had a lower viral load, exhibited less inflammation and tissue damage, and were less likely to die from viral infection, confirming that BGE-175 works through the PGD2 pathway.
Co-corresponding author Stanley Perlman, Ph.D., Professor of Microbiology and Immunology at the University of Iowa, said, "Our findings clearly show that the therapeutic target of BGE-175 plays a key role in making the aging lung environment conducive to optimal immune function, thereby fighting immune aging. The protective effect of the drug in mouse models supports the idea that BGE-175 corrects for age-related immunity decline, providing a strong justification for testing in elderly patients hospitalized for COVID-19. ”
Clinical applications in human COVID-19 and other diseases
A Phase 2 clinical trial launched in March 2021 is testing whether BGE-175 can prevent respiratory failure and death in elderly patients hospitalized with COVID-19. Since some cases of COVID-19 are associated with uncontrolled inflammation, which increases the severity and incidence of the disease, the clinical trial will also measure the effect of BGE-175 on inflammatory marker levels to gain insight into BGE-175's ability to restore normal regulation of the immune system.
Antiviral drugs against COVID-19, as well as antibodies produced by vaccines, all bind to specific viral proteins to exert their effects, so if the SARS-CoV-2 virus continues to mutate, they may lose efficacy, as the highly contagious Omicron variant has been observed.
Because BGE-175 targets the host's immune system rather than the invading SARS-CoV-2, it has the potential to maintain efficacy against new strains that are able to resist antiviral drugs or evade vaccine immunity. Similarly, since the drug's mechanism of action is not specific to COVID-19, it may help older patients fend off other viruses. Consistent with this, in this new study, BGE-175 prevented the lethality of the coronavirus SARS-CoV, which, like SARS-CoV-2, causes more severe disease in older animals.
Dr Eric Verdin, president and CEO of the Buck Institute on Aging (who was not involved in this new study), said, "A functioning immune system is our first line of defense against any virus, and we know that age-related immune abnormalities greatly increase the risk of death and complications of COVID-19 in older adults." New therapies that target age-related pathways, especially those involving immunity, will provide important tools to reduce the burden of death and disability from COVID-19 and other infections that overly harm older adults. ”
Pending the positive results of this Phase 2 clinical trial, BioAge Laboratories intends to pursue a wide range of clinical applications for BGE-175, including diseases such as influenza and viral pneumonia.
