image of lungs with SARS-CoV-2 particles on them to indicate infection and lung damage from COVID-19
Credit: Peter Zelei Images / Getty Images

A molecular “decoy” provided long-term protection from SARS-CoV-2 infection in mice, in a new study. The researchers created a version of ACE2, the surface protein the virus attaches in peoples’ airways. The free-floating decoy binds the virus, soaking it up before it can infect the airway. Treatment with the decoy, either by injection or droplets in the nose, protected 100 percent of the study mice when they were infected with an otherwise lethal dose of SARS-CoV-2.

The work was led by researchers at NYU Grossman School of Medicine and appeared this week in the Proceedings of the National Academy of Sciences.

“What is remarkable about our study is that we delivered the decoy using a harmless, adeno-associated virus or AAV vector, a type of gene therapy that has been found in previous studies to be safe for use in humans,” says senior study author Nathanial Landau, PhD, a professor in the Department of Microbiology  at NYU Langone Health.

SARS-CoV-2, the virus that causes COVID-19, uses its spike protein to attach to a protein on the surface of angiotensin converting enzyme 2 (ACE2) cells in airways. The virus can then enter the cell to hijack its machinery and make viral copies.

Earlier in the pandemic, pharmaceutical companies designed monoclonal antibodies to attach to the spike and neutralize viral particles. Treatment of patients soon after infection helped prevent hospitalization and death.

However, the virus rapidly evolved through random mutations that altered the spike’s shape enough to evade even combinations of therapeutic monoclonal antibodies. Thus, such antibodies became about 300 times less effective against more recent delta and omicron variants.

Unlike monoclonal antibodies, which interfere with a certain spike shape, the decoy mimics the spike’s main target, the ACE receptor.

In this study, the decoy lowered the virus load in the mice by 100,000-fold, while mice exposed to a non-active control treatment died. Whether it was administered via injection into muscle, or through droplets in the nasal cavity, the study’s AAV vectors provided mice with long-lasting protection from COVID infection, including the current Omicron variants.

Decoy treatment of mice that were already infected with SARS-CoV-2 caused a rapid drop in viral levels and return to health. This suggests that the decoy could be effective as a therapy post-infection, similar to monoclonal antibodies, the researchers say.

“The viral vector instructs cells in the body to produce the decoy so that the mouse or person is protected long-term, without the need for continual treatment.” said Landau. The treatment caused cells not only to make the decoy, but to continue making it for several months, and potentially for years.

The research team made key changes to a free ACE2 receptor molecule, and then fused the spike-binding part of it to the tail end of an antibody with the goal of strengthening its antiviral effect. Attaching ACE-2 to the antibody fragment to form what the team calls an “ACE-2 microbody” increases the time that the molecule persists in tissues. The combination also increases the strength with which the decoy attaches to the viral spike.

While more work needs to be done, “ The approach could be valuable for immunocompromised individuals and would be useful in the event of zoonosis of a future coronavirus,” the researchers write.

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