Courtesy of Yale Medical School
There may soon be a treatment for the leading cause of congenital birth defects in the United States, new research from the Yale School of Medicine suggests.
A study published in the journal “Virology” on Sept. 19 reveals the ability of two mood stabilizing drugs — valpromide and valnoctamide — to counter the symptoms of cytomegalovirus (CMV), an often latent virus that is particularly dangerous in patients with weak immune systems.
After infecting a pregnant mother, CMV can cross the placenta and infect a developing baby, causing severe defects in hearing, vision and cognitive functions. The antiviral drugs now used to fight CMV are not recommended for pregnant women, as the drugs are known to induce birth defects. However, the discovery of valpromide and valnoctamide’s inhibitory effect towards the virus brings optimism to those in search of a treatment.
“I think it’s a hypothetical treatment for CMV-induced birth defects,” said Anthony van den Pol MED ’77, a professor of neurosurgery and psychiatry who served as the senior officer for the research.
“The hope is that something like valnoctamide, which has efficacy and appears safe in fetal animals, may actually be usable to treat [pregnant] mothers with active CMV infections.”
The team that made the discovery, composed of six researchers from various departments in the medical school, had learned that the drug valproate, similar in structure to the two mood stabilizers, had an inhibitory effect on Epstein-Barr Virus (EBV), which shares characteristics with CMV.
The realization prompted the scientists’ curiosity, said van den Pol, and in March 2015, the researchers began testing the effect of valpromide and valnoctamide on young CMV-infected mice. Although they expected to see some effect on CMV, they were surprised to observe the same inhibitory quality towards CMV that had been observed of valproate in EBV when their first experiments concluded four months later.
Sara Ornaghi, a gynecology and obstetrics researcher from the University of Milano-Biocca in Italy, designed and carried out most of the experiments in the study.
“We wanted to test these drugs just to see if there was an effect on CMV, but we didn’t expect such an inhibitory effect, such a big innovation,” she said.
The mice in the study’s experiments were induced with a severe prenatal infection; those that did not receive the drugs being tested had a 20 percent chance of survival, whereas the mice treated with the drugs had a 70 percent chance of survival.
Mice who received valpromide and valnoctamide also showed a better overall physical maturation. According to van den Pol, it seemed that the drugs were able to rescue the body from the effects of CMV for the most part.
Ornaghi’s previous experience working in clinics for prenatal infections largely inspired her to pursue treatment for congenital CMV, she said, adding that during her time interacting with women under her care, it was “really frustrating” when faced with a pregnant patient infected with the virus and to have no treatment.
After connecting with Michael Paidas, a professor of obstetrics, gynecology and reproductive sciences, Ornaghi was introduced to van den Pol, who has studied CMV for nearly 20 years. After confirming the long-term effects of the studied drugs in February of 2016, it seemed that she and the others had come very close to finding a solution to her frustration.
“We’ve taken a drug that is not teratogenic [related to or causing developmental malformations] and shown that at least in the animal it can prevent CMV infection,” said Paidas, who also contributed to the study. “That has enormous implications for pregnancy.”
The study also revealed that the drugs are able to inhibit CMV using very small doses and that they utilize a completely different mechanism of action than antiviruses currently prescribed. This means that valpromide and valnoctamide have the potential to fight strains of CMV that are resistant to current antivirals.
Both Ornaghi and Paidas said they see the drugs’ potential use in multiple-drug therapy of CMV, meaning they could combine the strengths of current antivirals with valpromide and valnoctamide. This is similar to a HIV treatment method, estimated to have saved 700,000 lives in 2010 alone, according to the National Institute of Allergy and Infectious Diseases.
Lynn Enquist, professor of molecular biology and neuroscience at Princeton University, praised the study.
“There are no significant issues with the data or the conclusions,” he said, adding that it may be some time before the new directions for drug discovery offered by the study prove productive.
Professor of laboratory medicine and epidemiology at the University of Washington Anna Wald told the News that the step between a mouse study and a treatment for humans is large, but the research is a necessary step in the right direction.
The authors of the study said that they are looking forward to continuing their research in order to test valpromide and valnoctamide’s potential use in the treatment of humans.
Because the two drugs are already approved for the treatment of mood disorders in human patients, the authors indicated that they are optimistic that a possible treatment could reach the public in a relatively short amount of time. Van den Pol said that, whereas the normal timeline for advancing potential treatment could span 10 to 15 years, these drugs might take only one-fifth as long.
It is estimated that CMV infects nearly 85 percent of the American population, although the majority of infected men and women never show symptoms and lead healthy lives.