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A New Class of Antiviral Therapy Could Treat COVID-19
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Article | By Julie Langelier | December 9, 2021
As the SARS-CoV-2 virus mutates, new variants emerge that can better evade immunity and spread more widely. This causes an ongoing race, in which scientists and pharmaceutical companies must continually test and adapt vaccines to keep up with the latest variant of the virus. This is similar to how the flu vaccine must be redesigned each year to match the newest strains-except that SARS-CoV-2 evolves faster than the flu.
Using a fundamentally different approach, scientists at Gladstone Institutes and VxBiosciences discovered a new type of antiviral that can track the evolution of the virus, which significantly reduces the chance that new variants could reduce the efficacy of the treatment.
In a new study published in the journal Cell, the researchers engineered a single-dose treatment for SARS-CoV-2 that can be delivered intranasally. Their novel approach is based on the concept of therapeutic interfering particles, often called TIPs, which was pioneered by Gladstone Senior Investigator Leor Weinberger, PhD.
Viral-deletion mutants that conditionally replicate and inhibit the wild-type virus (i.e., defective interfering particles, DIPs) have long been proposed as single-administration interventions with high genetic barriers to resistance. However, theories predict that robust, therapeutic DIPs (i.e., therapeutic interfering particles, TIPs) must conditionally spread between cells with R0 >1. Here, we report engineering of TIPs that conditionally replicate with SARS-CoV-2, exhibit R0 >1, and inhibit viral replication 10- to 100-fold. Inhibition occurs via competition for viral replication machinery, and a single administration of TIP RNA inhibits SARS-CoV-2 sustainably in continuous cultures. Strikingly, TIPs maintain efficacy against neutralization-resistant variants (e.g., B.1.351). In hamsters, both prophylactic and therapeutic intranasal administration of lipid-nanoparticle TIPs durably suppressed SARS-CoV-2 by 100-fold in the lungs, reduced pro-inflammatory cytokine expression, and prevented severe pulmonary edema. These data provide proof of concept for a class of single-administration antivirals that may circumvent current requirements to continually update medical countermeasures against new variants.
He and his team report the discovery of the first TIP, showing it can inhibit SARS-CoV-2 and its variants, and withstand the virus's ability to evolve new resistant variants. They showed, in animals, that TIPs dramatically reduced the amount of SARS-CoV-2 virus found in the lungs and protected the animals from disease.
"The past 2 years have impressed upon the world how much we need new antiviral strategies," says Harmit Malik, PhD, professor at the Basic Sciences Division at Fred Hutchinson Cancer Research Center in Seattle, who was not involved in the study. "The design and use of TIPs has always held incredible promise of providing a simple-to-administer, highly effective antiviral strategy that can resist viral adaptation. This study is a true inflection point, showing that the powerful TIPs technology is not just theoretically possible, but imminently within reach."
A New "Hijacker" Therapy
When a virus like SARS-CoV-2 infects a cell, it takes over the cell's machinery and transforms it into a factory to produce more virus. TIPs are designed to exploit the virus's machinery, converting the infected cell from a virus-producing factory into a therapy-producing factory. If the virus is said to hijack the cell, the TIP "hijacks the hijacker."
And as the virus evolves, TIPs adopt the same mutations as the virus in order to survive, because they need the virus's machinery to replicate. As a result, TIPs continually track the virus's evolution.
"Viruses are dynamic, they mutate, yet our current medical countermeasures are static-there is a fundamental mismatch between our tools and the diseases we're trying to treat," says Weinberger, William and Ute Bowes Distinguished Professor, director of the Center for Cell Circuitry at Gladstone, and professor of biochemistry and biophysics, and pharmaceutical chemistry at UC San Francisco. "Ultimately, if we want to effectively control viruses like SARS-CoV-2, we will need therapies that bridge this mismatch and keep up with the virus as it evolves."
Weinberger's team has now developed a TIP for SARS-CoV-2-the first antiviral with the capacity to track viral evolution.
In the study, the researchers tested the TIP in cells derived from patients. Using lipid nanoparticles (similar to how mRNA vaccines from Moderna and Pfizer are delivered), they also delivered the TIP as a single dose in the nose of live infected hamsters, either before or after infection. The treatment reduced the viral load in the lungs by 100-fold. They found that TIPs prevented disease by reducing the number of viral particles released from an infected cell. TIPs also reduced the inflammation that can cause many COVID-19 complications and prevented pulmonary edema, the main driver of COVID-19 related deaths. What's more, only the single dose was required since TIPs could spread their antiviral properties to new cells when the virus was present.
The researchers then demonstrated that TIPs are effective against variants of SARS-CoV-2. They specifically tested the Alpha variant first identified in the United Kingdom and the Beta variant first identified in South Africa, as well as TIPs' potential against the SARS virus that spread in 2003. They are now testing against new variants.
"Our study provides proof-of-concept that TIPs could overcome the need to constantly update our therapies and vaccines to fight against new virus mutations," says Sonali Chaturvedi, PhD, first and co-corresponding author of the study and research investigator at Gladstone. "In the case of SARS-CoV-2, this single-administration intranasal treatment could provide longer lasting protection against the virus and its variants than current vaccines."
Decades in the Making
More than two decades ago, while Weinberger was a graduate student, he proposed the theoretical underpinnings of the TIP concept and how to engineer them, based on discoveries from the 1950s by a Danish microbiologist showing that viruses form defective particles that "piggyback" to interfere with viral replication. The term "TIP" was coined in a follow-up paper published by Weinberger in 2011.
The idea for TIPs was conceived to address problems in HIV treatment with an approach that could overcome antiviral drug resistance and act as a single-administration therapy. It was specifically designed to treat the highest-risk populations in the most resource-limited settings, such as sub-Saharan Africa.
When the COVID-19 pandemic hit, Weinberger and his team were approached by the US government, who was funding their HIV clinical trials, to repurpose the TIP approach to the SARS-CoV-2 virus.
The team is now working in collaboration with VxBiosciences to rapidly move TIPs for both HIV and SARS-CoV-2 to clinical trials, which are already funded by the National Institutes of Health and the US Department of Defense.
"These data show for the first time that the interfering particle concept is a reality in vivo, opening the door for a new class of antivirals that should be broadly applicable when tailored for different viruses," says Nancy Haigwood, PhD, professor and director of the Oregon National Primate Center, who was not involved in the research. "The current study clearly demonstrates mitigation of inflammation and disease in a relevant model for SARS-CoV-2, and the use of single-dose nasal delivery is icing on the cake. It is welcome news for a disease that has battered the planet's inhabitants since 2019."

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