Scientists at Oregon State University have developed a new treatment for COVID-19. The technology is based on mRNA, which has also been put to good use in COVID-19 vaccines. However, in this instance, the delivered mRNA encodes for human angiotensin-converting enzyme 2 (hACE2), which is the binding site for SARS-CoV-2 on airway cells.
The lipid nanoparticle-encapsulated mRNA therapeutic is delivered to cells in the body, and then the cells begin to produce and release a free-floating form of hACE2 that acts as a decoy to soak up viral particles. Once the viral particles are bound to the decoys, they are no longer available to bind to cells in the body, and their mischief is over. Excitingly, the technology works with different variants of the virus, suggesting it could form a useful universal treatment.
Messenger RNA has proven its worth as a COVID-19 vaccine technology, but researchers are interested in taking things a step further by using mRNA as a COVID-19 treatment. Moreover, given the ability of the virus to mutate and evade our immune system, developing treatments that help to combat new variants is important, and these Oregon State researchers believe that mRNA therapeutics represent a way to achieve this.
“Rather than messenger RNA as a vaccine, this shows that mRNA can be used as a universal therapy against different coronaviruses,” said Gaurav Sahay, one of the developers of the new technology. “Despite mass vaccination, there is an urgent need to develop effective treatment options to end this pandemic. Several therapies have shown some effectiveness, but the virus’ high mutation rate complicates the development of drugs that treat all variants of concern.”
The key to bypassing the advantages provided by viral mutation is not to target the virus itself, but rather to present it with a decoy version of its binding site in the body. No amount of mutation is likely to change the fact that SARS-CoV-2 must bind to hACE2 to enter target cells. To achieve this, the researchers developed an mRNA therapeutic that stimulates cells to begin producing a soluble form of hACE2 that will float around the body and mop up SARS-CoV-2 particles.
Another option is to deliver the treatment straight to the lungs as an inhalational therapy, meaning that airway cells would produce their own decoys, providing a first line of defense in the place it is most needed. So, why not just administer hACE2 to patients in protein form, and skip the mRNA stage? The hACE2 protein has a short half-life in the body and therefore won’t be effective for long. However, in the context of an mRNA therapy that codes for hACE2, treated cells can create their own hACE2 for an extended period, providing effective treatment for longer.
“The soluble enzyme effectively inhibited live SARS-CoV-2 from infecting host cells,” said Jeonghwan Kim, another researcher involved in the study. “The synthesis of mRNA is fast, affordable and scalable, and lipid nanoparticle-delivered mRNA can be repeated as necessary to sustain protein production until the infection subsides. Once treatment stops, the no-longer-needed soluble hACE2 clears the system in a matter of days.”
Study in Advanced Science: Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS-CoV-2