Sex differences a rich field for UCLA multiple sclerosis researcher
As a child, Dr. Rhonda Voskuhl had terrible asthma, was often sick and had to get weekly allergy shots. She wondered why her body was so reactive to pollen, cats, wheat and eggs — her throat would swell, breathing became more difficult and her skin developed a rash. A frequent visitor to the doctor’s office, she had “a wonderful doctor who made me feel so much better.”
It’s no surprise, then, that Voskuhl grew up to become a doctor. Today, Voskuhl directs UCLA’s multiple sclerosis program and is the Jack H. Skirball professor of Multiple Sclerosis Research. She’s wrapping up one clinical trial and eager to start another, all while deepening her knowledge of microscopic mechanisms in multiple sclerosis through preclinical research in the lab.
Because of her asthma, Voskuhl wanted to study autoimmune diseases, in which the body’s immune system attacks healthy cells. These diseases include asthma, multiple sclerosis, lupus, inflammatory bowel disease and rheumatoid arthritis — most of which occur more often in women.
Early in her career, there was little interest in the scientific community about why diseases might behave differently in men and women. She tells the anecdote of how, about 25 years ago, while conducting a mouse study as a postdoctoral fellow, her supervisor told her to use only female mice for the experiment. Male mice were a waste of money, he told her, because they were less likely to get sick.
“I said, ‘But that’s kind of interesting, isn’t it? Like, why are females more susceptible?’ He said, ‘Nah! Just order the females and do the experiment,’” Voskuhl said. “And that’s when I decided I wanted to study the sex difference in multiple sclerosis.”
In 2016, when the National Institutes of Health announced a new requirement that all NIH-funded, preclinical studies include females and males, the agency cited Voskuhl’s findings in sex differences in MS as a rationale for the new policy.
Multiple sclerosis is a progressive, neurodegenerative disease that causes physical weakness and cognitive difficulty, among other symptoms. The body’s immune cells destroy myelin, the protective insulation that allows electrical signals to be conducted through nerve fibers. Without myelin, nerve signaling fails, and nerves become damaged and die. Relapses are temporary disabilities that occur when waves of immune cells enter the brain and spinal cord. Over the years, permanent disabilities emerge, even without relapses.
In MS, the difference between men and women is pronounced. Women get the disease three to four times as often as men do, but men typically develop permanent disabilities more quickly.
Another intriguing difference is that women with multiple sclerosis have long reported that they feel better and have fewer relapses during pregnancy. The reason for this is unclear. Voskuhl and other researchers have suspected that this might be due to estriol, an estrogen produced by the fetus and placenta in pregnancy. In mouse models, estriol treatment was protective. Estriol is used extensively in Europe for treating menopausal symptoms.
In a study led by Voskuhl and published in 2016 in the journal Lancet Neurology, women with multiple sclerosis who were treated with estriol had fewer flare-ups of symptoms than women who weren’t treated with estriol. There was also evidence of improvement in cognition and a reduction in fatigue, as well as prevention of atrophy in important regions of the brain. Voskuhl is now planning a larger, late-stage clinical trial.
In addition, Voskuhl is completing enrollment of a mid-stage trial of estriol treatment for MS that will focus on cognitive impairment in the study participants.
“The beauty of estriol is it both reduces inflammation and repairs damage in the brain and spinal cord, acting in a way that is new and different from other MS drugs. This is important for patients since it means it could improve disabilities, not merely slow worsening,” Voskuhl says.
Voskuhl, an inventor on a UCLA patent for use of estriol to treat multiple sclerosis, has been working on a “next-generation estriol” for more than a decade. She recently began working with a UCLA chemist to develop versions of the compound that are superior to what is currently available.
The UCLA Technology Development Group is now offering to license UCLA patents for estriol and the next generation compounds to outside companies interested in developing them into medications that can benefit patients.
Voskuhl’s work with estriol, as well as with a disease that has a dramatically different effect on women and men, has made her a staunch advocate of including males and females in studies. Though just 25 years ago a study of sex differences in a disease was thought of as an unnecessary expense, today those differences are increasingly recognized as rich territory for discovery.
“Study the differences, don’t just ignore them,” Voskuhl says. “It can lead to some really interesting treatments.”