BURSTViruses are all around us. These pathogens can sneak past our immune systems and blitz us with infections that lay us out for days or weeks on end. While some viruses eventually resolve on their own, others can lead to serious illness and even death. Even today, the flu kills 3,000 to 50,000 people a year in the United States, especially children and the elderly. And of course, COVID-19 took the lives of millions of people around the globe. It seems as though every two to three years, a highly contagious, often deadly, viral disease emerges that leads to a new epidemic.
So far, scientists have struggled to identify compounds that could be used as universal antivirals, capable of fighting a large number of viral infections in one fell swoop. But recently, scientists took inspiration for such a super drug from a quiet corner of the medical world: The small subset of people with a rare autoimmune condition called ISG15 deficiency, for whom viruses have almost no impact.
The autoimmune disorder, which typically impacts infants and young children, is caused by a deficiency in an immune system regulating molecule called, unsurprisingly, ISG15. The deficiency creates a state of persistent, low-level inflammation in the body that can lead to skin lesions, neurological complications, and adverse reactions to certain vaccines. But that inflammation also has an upside: It protects these patients against most viral infections.
Columbia University pediatric immunologist Dusan Bogunovic and some of his colleagues recently decided to investigate whether they could harness this power to protect people who don’t have the disorder against viral infection. In August, they published their findings in the journal Science Translational Medicine. In this experimental work, the team tested a potential drug on human cells as well as mice and hamsters and found that it provided protection against a number of viruses, including those that cause Zika, COVID-19, and some strains of influenza. This drug could even play a crucial role in mitigating infections from unknown viruses during the next global pandemic, Bogunovic says.
While the drug would work similarly to a vaccine to provide preventive immunity, Bogunovic says that the mechanism is actually very different. Instead of introducing an inactivated virus or a small piece of a virus, like vaccines typically do, this approach would introduce genes already naturally synthesized in the human body.
The drug could even play a crucial role in mitigating infections from unknown viruses during the next global pandemic.
“What we did is essentially synthesize genes that our body normally synthesizes,” says Bogunovic. “There is no class of drugs in which we essentially use our own genetic code … to fight our viral functions.”
When a person is exposed to a virus in the wild, this can trigger upwards of thousands of gene responses, Bogunovic says. This is part of what makes us feel so lousy. To create a low-level inflammatory response that mimics that of ISG15 deficiency, the research team isolated just 10 genes that are the most crucial for launching that inflammatory response. Using mRNA techniques, these genes were then packaged into a lipid nanoparticle to be deployed first on a human cell culture and then animal models.
In their first test on human cells, Bogunovic says they observed an immune response that was orders of magnitude greater than placebo alone. This was an “oh wow,” moment, he says.
The team next moved on to animal trials where they gave groups of mice and hamsters both a strain of influenza and SARS-CoV-2 (which causes COVID-19) respectively. A portion of each animal group was then administered the antiviral drug while the other portion received a placebo drug. In these trials, the mice who took the antiviral had 1,000 times more protection against the flu virus than placebo alone, Bogunovic says. But the hamsters fared even better.
“Basically, we gave [the] hamsters so much virus that those that received placebo started dying,” he says. The hamsters that received their drugs, on the other hand, had a little bit of malaise but were then cured.
Carl Nathan, a professor of medicine at Weill Cornell Medicine who was not involved in this research, said the findings are promising. “The result [of this research] is a resounding vindication of the effort to study, in depth, individuals 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 research, agreed, given the lack of existing universal therapies to treat viral infections.
In the future, Bogunovic imagines this drug as something that a person may be able to take weekly or even monthly via an inhaler or topical cream to protect against almost any virus. However, there are some obstacles to reach that future—both scientific and societal.
Nathan and Cooper both agree that safety and efficacy will need to be tested in future human trials. In particular, researchers will need to ensure that these 10 genes do not produce a toxic effect when administered via the mRNA crafted nanoparticle, says Nathan.
But Bogunovic worries that in a political climate that is anti-mRNA and anti-vaccine, it will be difficult to advance this drug as a potential tool to combat the next pandemic.
“In the context of anti-infective development and anti-viral development, it has become clear that we truly need government and state support for this to become a reality,” says Bogunovic. “The sheer market forces are not enough.” 
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