Editing out a particular gene located inside cells has big implications for the weakening of the common cold virus along with more dangerous infectious agents.
When it comes to warding off the common cold, people can do little more than be scrupulous about handwashing and avoid sick friends and colleagues. Now, a team of researchers believes it has hit upon a potential way to stop cold viruses from causing potentially serious illness in people, especially those who suffer from asthma.
Investigators at Stanford University, along with partners at the University of San Francisco, cultured 20,000 human cells, including lung cells, and used CRISPR-Cas9 technology to edit out different genes inside them. All of the edited cells then were screened (infected) with rhinovirus C15 (RV-C15) and enterovirus D68 (EV-D68), which is implicated in outbreaks of acute flaccid myelitis, to see if the absence of any particular gene made a difference in how the viruses behaved.
When the results from the RV-C15 and EV-D68 screenings were overlaid, it became clear that 1 particular gene, SETD3, changed the behavior of both viruses: There was a 1000-fold reduction in the amount of viral replication happening in the cells in which SETD3 was disabled. The investigators realized this could have broad implications for the continuing development of medications that act against the common cold and other illnesses.
To confirm the results of their cell testing, the team members edited SETD3 out of mice genes and then injected 2 viruses that can cause paralysis and death directly into their brains. The bioengineered mice saw much lower levels of viral replication than expected and remained completely healthy.
“Our approach is instead of targeting the virus directly, we want to target the host,” Jan Carette, PhD, associate professor in the Department of Microbiology and Immunology at Stanford University School of Medicine, and a senior author of the study, told Contagion®. “We want to make the host inhospitable to infection.” One way to do that might be to create a drug that targets a person’s SETD3 gene rather than the virus itself.
Ideally, such a drug would prevent a multitude of potential ailments. Carette explained that EV-D68, which has been responsible for many cases of the somewhat mysterious acute flaccid myelitis epidemic afflicting a small number of children every 2 years, is structurally very similar to RV-C15 and responded similarly to the absence of SETD3 during cell testing. Other viruses, such as Zika and dengue, however, were impervious to the altered gene. “The gene seems to be very specific for broad classes of viruses that causes the common cold and also paralytic diseases,” he said.
The effects of editing out SETD3 are unknown in humans, so Carette’s team plans to continue research in this area. One goal is to temporarily disable SETD3 rather than do away with it completely, particularly so that people with asthma, in whom the common cold can exacerbate respiratory symptoms, are less at risk during cold and flu season. If a broad-spectrum drug is developed that can target SETD3, it could protect people not only from colds but from viruses that cause paralysis such as acute flaccid myelitis.
“For asthmatic patients, if a family member is sick, maybe they could take it prophylactically,” Carette said of a possible new drug. As far as protecting the general population from colds or paralytic conditions, Carette has high hopes for that, too. “If the drug is safe, it could be one day offered over the counter,” he mused.
In addition to Carette, senior authors of the study include Or Gozani, MD, PhD, a professor of biology at Stanford, Raul Andino, PhD, a professor of microbiology and immunology at UCSF, and Nevan Krogan, PhD, professor of cellular and molecular pharmacology at UCSF.