New "universal" COVID-19 treatments

A study led by a pharmacy researcher at Oregon State University demonstrated the principle
of a new "universal" approach to treating COVID-19.

Gaurav Sahay and his collaborators at Oregon State University and the Texas Biomedical Research Institute demonstrated in a mouse model that it is possible to prompt the production of a protein that can block multiple variants of the SARS-CoV-2 virus from entering cells and causing respiratory disease
.

Sahay said: "This suggests that messenger RNA can be used as a universal therapy against different coronaviruses, not as a vaccine
.
Despite mass vaccination, there is an urgent need to develop effective treatment options to end the pandemic
.
Several therapies have shown some effect, but the high mutation rate of the virus complicates
the development of drugs to treat various diseases.
”

The findings were published in
the journal Advanced Science.
The next step, Sahay said, is to prove that the protein can prevent infection in mice, adding that the mRNA therapy could be "years" away from being applied to human patients
.

Inhalation of the virus is the leading way to contract COVID-19, with 6 million people dying
worldwide since the pandemic began in late 2019.
The envelope of the virus is covered with the spike protein, which binds
to an enzyme produced by the cells of the lungs.

By using messenger RNA packaged in lipid nanoparticles, the scientists showed in mouse models that host cells can produce a "decoy" enzyme that binds to the coronavirus spike protein, meaning the virus should not be able to attach to cells in the host airway and initiate the infection process
.

The study, which involves intravenous injection and inhalation of messenger RNA, would be the preferred method of delivery in humans, was published in
Advanced Science.

Sahay, an associate professor at Oregon State University's School of Pharmacy, said: "Proteins are large, complex molecules that are the backbone of the cell, enabling all the biological functions within the cell to be realized
.
" "After encoding the first transcribed into messenger RNA, DNA holds the blueprint
for protein synthesis.
"

An enzyme is a protein that is a catalyst
for biochemical reactions.
HACE2, short for human angiotensin converting enzyme 2, is an enzyme
in airway cells.
It is also expressed in the heart, kidneys, and intestines and is involved in many physiological functions
.

Simply giving hACE2 to COVID-19 patients has limited effect on treating the disease because the soluble form of the enzyme, the kind that can circulate throughout the body, has a short half-life — less than two hours, meaning it doesn't stay in a person's system for a long time
, Sahay said.

But lipid nanoparticles, often abbreviated as LNPs, contain messenger RNA produced by command enzymes that can help overcome this problem
.

In this study, the researchers designed synthetic messenger RNA to encode a soluble form of the enzyme, packaging the messenger RNA into lipid nanoparticles and delivering it into liver cells via intravenous injection; Within two hours, the enzyme entered the mice's bloodstream and stayed there for several days
.

The scientists also delivered loaded LNP through inhalation, prompting epithelial cells in the lungs to secrete soluble hACE2
.

Jeonghwan Kim, a postdoctoral researcher at Ohio State University, said: "This soluble enzyme effectively inhibits live SARS-CoV-2 infection of host cells
.
" mRNA synthesis is rapid, inexpensive, and scalable, and lnp-delivered mRNA can be repeated as needed to maintain protein production until the infection resolves
.
Once treatment is stopped, soluble hACE2 that is no longer needed is cleared from the system
within a few days.
”

In addition to Sahay, other OSU scientists include Jeonghwan Kim, Antony Jozic, Anindit Mukherjee and Dylan Nelson
.
The study with live viruses was conducted in collaboration with scientists Kevin Chiem, Md Siddiqur Rahman Khan Jordi B.
Torrelles and Luis Martinez-Sobrido at the Texas Biomedical Research Institute

Jeonghwan Kim, Antony Jozic, Anindit Mukherjee, Dylan Nelson, Kevin Chiem, Md Siddiqur Rahman Khan, Jordi B.
Torrelles, Luis Martinez‐Sobrido, Gaurav Sahay.
Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS‐CoV‐2.
Advanced Science, 2022; 2202556