A novel COVID-19 therapy that is breathed prevents viral multiplication in the lungs

A novel COVID-19 treatment developed by researchers at the University of California, Berkeley may one day make treating SARS-CoV-2 infections as simple as using an allergy nasal spray.

The treatment interferes with the genetic machinery that permits SARS-CoV-2 to replicate in the body by using brief synthetic DNA snippets.

The team demonstrates that these little pieces, known as antisense oligonucleotides (ASOs), are very successful at preventing the virus from replicating in human cells in a recent study that was published online in the journal Nature Communications. These ASOs work well to both prevent and treat COVID-19 infection in mice and hamsters when given intravenously.

“Vaccines are making a great effect, but they are not ubiquitous, and there is still a tremendous need for new treatments,” said Anders Näär, professor of metabolic biology in the Department of Nutritional Sciences and Toxicology (NST) at UC Berkeley and the paper’s senior author. An inexpensive nasal spray that is widely accessible and may assist someone avoid contracting an infection or a serious sickness would be tremendously beneficial.

All of the SARS-CoV-2 “variants of concern” are resistant to the ASO treatment in human cells and animal models because it specifically targets a region of the viral genome that is highly conserved across different variants.

It is also reasonably cheap to create in large quantities, chemically stable, and well-suited for treating COVID-19 infections in regions of the world without access to refrigeration or electricity.

The ASO method might be easily tweaked to target other RNA viruses if the treatment proved to be secure and efficient in humans. The study group is already looking into how to utilise this to prevent influenza viruses, which also have the ability to spread pandemics.

According to study first author Chi Zhu, a postdoctoral scholar in NST at UC Berkeley, “if we can design ASOs that target entire viral families, then when a new pandemic emerges, as long as we know which family the virus belongs to, we could use the nasally delivered ASOs to suppress the pandemic in its early stages.” The appeal of this novel therapy lies in that.

The viral copy machine being hacked

Similar to DNA, RNA also carries genetic information that is encoded in a series of base pairs, however unlike DNA, RNA typically only consists of a single strand without a second, complementary strand to form a double helix. However, complementary base pair sequences still enable RNA to attach them easily. ASOs are short strands of synthetic DNA-like molecules that have been engineered to adhere together like molecular Velcro.

ASOs are brief, synthetic DNA-like molecules that, like molecular Velcro, are engineered to adhere to particular RNA sequences in cells and viruses.

Näär and his team have been researching these compounds’ potential to alter messenger RNA and microRNA activity in the human body for more than 10 years in an effort to potentially reverse disorders like obesity, Type 2 diabetes, fatty liver disease, and Duchenne muscular dystrophy. His team immediately rallied to investigate if ASOs could also be utilised to obstruct SARS-CoV-2 when the COVID-19 outbreak struck.

According to Näär, the SARS-CoV-2 genome is single-stranded RNA, just like messenger RNA or microRNA. We reasoned that we might be able to attach these ASOs to the viral RNA and stop it from functioning.

The team started comparing the SARS-CoV-2 virus to hundreds of various ASOs in cooperation with the lab of associate professor Sarah Stanley at the UC Berkeley School of Public Health and Department of Molecular and Cell Biology, as well as researchers at the Innovative Genomics Institute. The iconic “spike” protein, which aids the SARS-CoV-2 virus in hijacking host cells, is encoded in a separate section of the viral RNA, which is what each of these ASOs was created to disrupt.

They chose one of these targets that was by far the best at preventing the virus from spreading. This target was a viral RNA non-coding region with a hairpin loop shape that is thought to be essential for SARS-CoV-2 replication.

We demonstrated that attaching an ASO to this hairpin breaks the hairpin, causing the RNA to form a straight line as opposed to a bubble structure. We discovered that it was highly successful at preventing viral replication in human cells, and we believe that doing so prevents the virus from effectively translating and replicating.

The team discovered that ASOs were also very successful at preventing and treating COVID-19 infections when they were given into the noses of infected hamsters and mice. These studies also revealed that the ASOs did not appear to significantly stimulate the immune system, demonstrating that ASOs are unlikely to have hazardous side effects in people.

All known SARS-CoV-2 variants contain the hairpin loop structure, therefore ASOs ought to be effective against all of them. The scientists replicated their trials against all of the key variations of concern, including the highly contagious omicron and delta, to demonstrate that this is the case.

According to study author and UC Berkeley NST graduate student Justin Lee, “[SARS-CoV-2] enters the body and hijacks our own machinery to become a copy machine to make tonnes of virus copies for increased infection and dissemination.” All the variants, including delta and omicron, share the same key code, which was discovered in the viral RNA and enables the copy machine to function.


Before the ASO treatment is approved for human clinical trials, the team still needs to undertake more research. Näär is hopeful that the therapy will eventually be included in a range of therapies for COVID-19 and other viral diseases.

This pathogen is clearly not going away, according to Näär. “We need to approach it from many different angles, and therapies like ours that are indifferent to the variations could be quite important.”

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