INViruses surround us everywhere. These pathogens can sneak past our immune system and give us infections that kill us for days or weeks on end. While some viruses go away on their own over time, others can cause serious illness and even death. Even today, influenza kills between 3,000 and 50,000 people a year in the United States, especially children and the elderly. And of course, Covid-19 has killed millions of people around the world. It seems that every two to three years a highly contagious, often fatal viral disease emerges and results in a new epidemic.
Until now, scientists have tried to identify compounds that could be used as universal antiviral agents, capable of fighting a large number of viral infections in one fell swoop. But scientists recently found inspiration for such a superdrug in a quiet corner of the medical world: a small group of people with a rare autoimmune disease called ISG15 deficiency, who are largely unaffected by viruses.
The autoimmune disease, which typically affects infants and young children, is caused by a deficiency of an immune system-regulating molecule called, unsurprisingly, ISG15. Deficiency creates a state of persistent, low-grade inflammation in the body that can lead to skin lesions, neurological complications, and adverse reactions to some vaccines. But this inflammation also has a positive side: it protects patients from most viral infections.
Columbia University pediatric immunologist Dusan Bogunovic and some of his colleagues recently decided to see if they could use this power to protect people who Not have a disorder against viral infection. In August they published their conclusions in the magazine Scientific translational medicine. In this pilot work, the team tested the potential drug in human cells as well as mice and hamsters and found that it provided protection against a range of viruses, including those that cause Zika, COVID-19 and some strains of influenza. The drug could even play a critical role in mitigating the effects of infection by unknown viruses during the next global pandemic, Bogunovic said.
While the drug will work similarly to a vaccine to provide preventative immunity, Bogunovic says the actual mechanism is quite different. Instead of injecting an inactivated virus or a small part of a virus, as vaccines are typically done, this approach would introduce genes already naturally synthesized in the human body.
The drug could even play a critical role in mitigating the effects of unknown viruses during the next global pandemic.
“Essentially, we synthesized genes that our body normally synthesizes,” Bogunovic says. “There is no class of drugs where we essentially use our own genetic code … to target our viral functions.”
When a person is exposed to the virus in the wild, it can trigger thousands of gene responses, Bogunovic said. This is part of what makes us feel so lousy. To create a low-level inflammatory response that mimics ISG15 deficiency, the research team isolated just 10 genes that are most important for triggering this inflammatory response. Using mRNA techniques, these genes were then packaged into lipid nanoparticles, which were then used first in human cell culture and then in animal models.
Bohunovich says that in their first test on human cells, they observed an immune response that was orders of magnitude stronger than a placebo alone. It was an “oh wow” moment, he said.
The team then moved on to animal testing, where they gave groups of mice and hamsters a strain of influenza and SARS-CoV-2 (which causes COVID-19), respectively. Parts of each group of animals were then given an antiviral drug and the other part a placebo drug. In these trials, mice given the antiviral had 1,000 times greater protection against the influenza virus than a placebo alone, Bohunovich said. But the hamsters had even better luck.
“In essence, we gave [the] The hamsters had so much virus that those who received the placebo began to die,” he says.
Carl Nathan, a professor of medicine at Weill Cornell Medicine who was not involved in the study, said the results are promising. “Result [of this research] “This is a compelling endorsement of efforts to better understand people with rare diseases,” says Nathan. “The potential for medical benefit is high.” Megan Cooper, a professor of pediatric rheumatology at Washington University in St. Louis who also was not involved in the study, agreed, given the lack of existing universal treatments for viral infections.
In the future, Bogunovic envisions the drug as something a person could take weekly or even monthly via an inhaler or topical cream to protect against virtually any virus. However, there are some obstacles to this future, both scientific and social.
Nathan and Cooper agree that safety and effectiveness will need to be tested in future human trials. In particular, researchers will need to ensure that these 10 genes do not have toxic effects when administered via mRNA nanoparticles, Nathan says.
But Bogunovic is concerned that in the current political climate anti-mRNA and anti-vaccineIt will be difficult to promote this drug as a potential treatment for the next pandemic.
“In the context of developing anti-infectives and anti-virals, it became clear that we really needed government and government support to make this a reality,” says Bogunovic. “Market forces alone are not enough.”
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