Single-dose intranasal therapy also reduces symptoms of several SARS-CoV-2 virus variants
SAN FRANCISCO, September 9, 2022 /PRNewswire/ — By the time you test positive for COVID-19, the SARS-CoV-2 virus has already taken up residence in your respiratory system. With each breath you expel invisible virus particles into the air, a process known as viral shedding. Existing drugs aimed at treating COVID-19, even when treating the symptoms of the virus, do little to suppress viral shedding.
Gladstone Institute researchers have previously developed a new approach for the treatment of infectious diseases: a single-dose intranasal treatment that protects against severe SARS-CoV-2 infection.
Sonali Chaturvedi (left) and colleagues in Leor Weinberger’s lab at the Gladstone Institutes show that a new single-dose intranasal treatment for SARS-CoV-2 infection decreases viral shedding and limits virus transmission. Seen here with Daniela Lopez (right). Photo: Michael Short/Gladstone Institutes
In a new study published in Proceedings of the National Academy of Sciencesthey show that this new treatment, called therapeutic interfering particle (TIP), also decreases the amount of virus excreted by infected animals and limits virus transmission.
“Historically, it has been exceptionally difficult for antivirals and vaccines to limit transmission of respiratory viruses, including SARS-CoV-2,” says Gladstone lead researcher Leor Weinberger, PhD, lead author of the new paper. “This study shows that a single intranasal dose of TIP reduces the amount of transmitted virus and protects animals that have come into contact with that treated animal.”
“To our knowledge, this is the only single-dose antiviral that not only reduces symptoms and severity of COVID-19, but also virus shedding,” says Sonali ChaturvediPhD, researcher at Gladstone and first author of the article.
A drug that evolves
Viruses like SARS-CoV-2, as well as influenza and HIV, evolve over time, become drug resistant and make it difficult to develop long-lasting treatments. More than two decades ago, Weinberger first proposed the idea of therapeutic interfering particles (TIPs) to treat viruses; rather than directly targeting part of a virus, TIPs compete for resources within an infected cell. By monopolizing the replication machinery inside a cell, they can prevent the virus from making more copies of itself.
The benefit of TIPs, however, goes beyond their ability to quell a virus inside infected cells. Because TIPs reside inside the same cells as the virus they target, they evolve together, remaining active even when new viral strains emerge.
“Over the past few years, many of the challenges of the pandemic have been linked to the emergence of new variants,” explains Chaturvedi. “TIPs would be an ideal treatment because they continue to learn as the virus evolves, so they could get the drug resistance problem under control.”
Before the COVID-19 pandemic, Weinberger’s group was already developing TIPs to treat HIV. In 2020, they quickly turned their attention to SARS-CoV-2, developing a single-dose TIP against the virus that can be administered intranasally.
Last year, they reported that, in rodents, TIPs could successfully block several different variants of SARS-CoV-2, reducing viral load in the lungs by 100-fold and reducing many symptoms of COVID-19.
Stop the spread
In the new paper, Weinberger and Chaturvedi investigated whether TIPs could also reduce viral shedding — a separate issue from reducing symptoms and viral load.
The researchers treated hamsters infected with SARS-CoV-2 with the antiviral TIPs and then measured the amount of virus in the animals’ noses daily. Compared to hamsters that did not receive the TIPs (called control animals), the treated animals had less virus in their nasal passages at all times. On day 5, all control animals were still shedding high levels of virus, while virus was undetectable in four of five TIP-treated animals.
“We know that the amount of virus shedding is proportional to how infected a person is,” says Weinberger, who is also William and Ute Bowes Emeritus Professor and director of the Center for Cell Circuitry at Gladstone. “If viral shedding can be reduced, the number of secondary contacts who could become infected will also most likely be reduced, which in turn will decrease the overall spread of the virus and help keep vulnerable people safe.”
When SARS-CoV-2 infected animals were housed in cages with uninfected animals, treatment of infected animals with TIPs did not completely prevent COVID-19 transmission. However, this resulted in significantly lower viral loads and milder symptoms of infection in newly exposed animals.
“This particular laboratory setting is known to generate much more efficient transmission than typically seen in humans, even in domestic environments, as hamsters transmit not only via aerosols, but also via bodily fluids and by climbing on them. and grooming for many hours,” says Weinberger, who holds a professorship of biochemistry and biophysics and pharmaceutical chemistry at UC San Francisco. “So being able to reduce transmission of SARS-CoV-2 in this animal setting is quite promising for being able to reduce human-to-human transmission.”
While initial experiments were performed using the Delta strain of SARS-CoV-2, the researchers repeated the tests using the ancestral WA-1 strain of the virus and confirmed that the same TIPs were effective in all variants.
Weinberger’s team is now seeking FDA approval for a clinical trial to test TIPs in humans.
About the research project
The article “A single-dose therapeutic interfering particle reduces viral transmission and pathogenesis of SARS-CoV-2 in hamsters” was published in the journal Proceedings of the National Academy of Sciences on September 8, 2022.
Other authors are michael paul, Gustav Vasen, Xinyue Chen and Giuliana Calia of Gladstone; Nathan Beutler and Thomas Rogers from Scripps Research; David Smith from UC San Diego; and Lauren Buie and Robert Rodick from VxBiosciences, Inc.
The work was supported by Pamela and Edward Taftthe U.S. Army Medical Infectious Disease Research Program (MTEC 2020-492) and the National Institutes of Health (DP1DA051144).
About Gladstone Institutes
To ensure that our work does the greatest good, the Gladstone Institutes focus on conditions with profound medical, economic and social impact – unresolved diseases. Gladstone is an independent, not-for-profit life science research organization that uses visionary science and technology to defeat disease. He has an academic affiliation with the University of California, San Francisco.
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