For more than a decade, Harvard biomedical researchers Sonia Vallabh, J.D. ’11, Ph.D. ’19, and Eric Minikel, Ph.D. ’19, have been chasing a cure for prion diseases, a group of deadly neurodegenerative disorders for which the only current treatment is palliative care. This spring, they reached a new milestone, enrolling patients in a clinical trial for a new kind of drug, aimed at silencing the gene that causes the disease.
For Vallabh and Minikel, a married couple, this scientific development is also a personal one—and a race against the clock. In 2012, Vallabh learned that she had inherited the genetic mutation for fatal familial insomnia, one of several illnesses that fall under the prion disease umbrella.
Just over a year earlier, Vallabh’s mother had died from the disorder, falling suddenly ill at 51. Her first symptoms were blurry vision and weight loss, but soon she was having trouble remembering things and finishing her sentences. Severe and rapidly accelerating dementia was accompanied by increasingly serious physical decline: frequent falls, an inability to sit still, trouble sleeping. Vallabh told one interviewer that her mother seemed “stuck” between wakefulness and sleep. Within a few months she couldn’t feed or bathe herself, and not long after that, she was placed on life support.
The diagnosis of fatal familial insomnia came after her death. When Vallabh underwent genetic testing, she learned that she, too, was a carrier—a near-guarantee that she would one day develop the illness. She had recently earned a Harvard law degree and was working at a consulting firm, but within weeks of receiving the test results, she quit her job and returned to Harvard to study science full-time. The goal was to understand prion disease and find a cure in time to save her own life.
Minikel, a transportation analyst with an urban planning degree, soon joined her. After graduating from Harvard with doctorates in 2019, they opened their own laboratory at the Broad Institute, where they now co-direct the Prion Therapeutic Science program. By then, they’d already spent years in other labs researching possible therapies.
The new drug candidate, which has not been tested in humans before, is a type of molecule called a small interfering RNA (siRNA). Created from a molecular structure first developed by UMass Chan Medical School researcher Anastasia Khvorova, it works by cutting up the RNA in the body that encodes the prion protein, PrP. Prion disease develops when misfolded versions of this protein accumulate in the brain, forming plaques that destroy healthy tissue.
“The protein is the bad actor here,” says Minikel, “but it’s tough to target the protein once it’s there, so we want to go upstream and target the RNA molecule that makes the protein.”
Among the factors working in the researchers’ favor: if they find a therapy for one form of prion disease, it would work for all of them, since the same gene variant underlies every single case. “We think of it as one disease with different subtypes,” Vallabh says. “It’s an interesting example of precision medicine operating to unify things instead of subdivide them.” The most common prion disorder among humans is Creutzfeldt-Jakob disease, which kills about 500 people per year in the United States. Its symptoms are similar to fatal familial insomnia: dementia, vision problems, difficulty swallowing or speaking, loss of motor control, an inability to sleep.
The more relevant distinction for researchers is between people like Vallabh, who inherit prion disease, and the much larger population for whom it develops spontaneously, for no apparent reason. “Those patients won’t know that they have prion disease until they’re symptomatic,” Vallabh says. (In extremely rare cases, the disorder is transmitted through exposure to contaminated tissue; one example is mad cow disease.) Prion disease is rare, affecting only about one person per million worldwide, but it’s always fatal. Once symptoms begin, the disease progresses rapidly; most patients are dead within a year.
“So, one big challenge,” she says, “is to get people diagnosed as early as possible,” and to test for genetic mutations. Another is “to drive forward a trial and treatment paradigm in a preventive format, before people get sick.”
Minikel says the therapies they are researching would help both types of patients. Lowering the number of prion proteins in the brain would prevent or delay the disease in those who haven’t developed it yet and slow it down in those who have. “That’s the beauty of going after the root protein,” he says. In the newly launched clinical trial—funded by NeuroNEXT, a program within the National Institutes of Health—he and Vallabh are enrolling patients who are symptomatic.
“We’ve made a long-term commitment to advancing meaningful therapies for this disease,” Vallabh says, “and this is a rapidly evolving technological landscape. Compared to 10 or 15 years ago, there are many different technologies we can imagine to point at this one protein.”
The obligation for her and Minikel, she says, is to stay nimble to new information, to avoid getting hung up on any one potential therapy, and to keep going.
“Our constituency is patients like Sonia, and anything that moves the whole field forward, we want to do that,” Minikel says. The couple has made much of their research data public for other scientists to use.
“We’re building a runway,” Vallabh says, “that allows drug technologies to be tested efficiently and demonstrates to the world that we can get clear answers. That’s what makes it possible for lightning to strike.”
