RML scientists show experimental treatment slows deadly prion disease in mice

It’s not often that scientists working at the Rocky Mountain Laboratories in Hamilton have the opportunity to work beside someone their research can actually benefit.

And it’s even rarer that they are able to demonstrate that an experimental treatment may just hold the key to preserving their fellow researcher’s life.

Over the past five years, some of RML’s longest-tenured scientists studying prion diseases had an opportunity to do just that.

Back in 2014, Sonia Vallabh and her husband, Eric Minikel, gave up promising careers as a Harvard-trained lawyer and MIT-educated urban planner after they helplessly watched Vallabh’s mother die of an extremely rare prion disease called fatal familial insomnia (FFI).

The genetic sleep disorder begins with bouts of sleeplessness that quickly turns into complete insomnia, which rapidly causes mental and physical deterioration and eventually death.

In Vallabh’s mother’s case, the symptoms came suddenly. Just months before her death, she helped plan her daughter’s wedding. Shortly afterward, she began struggling to speak, had memory problems and began losing weight.

A few months later, she couldn’t walk or feed herself, and fell into a profound dementia. She was 52 when she died.

Until that point, no one knew exactly why.

Following an autopsy, a piece of her brain tissue tested positive for a mutation of a gene known to cause FFI. There had been no history of the neurodegenerative disease in her family.

Following her mother’s death, Vallabh decided to have herself screened. She learned she too carried the gene and would almost certainly develop and die from the disease unless treatments were found that would slow or stop its progression.

In 2015, she was 30. The average age of onset for the disease is 50.

The couple began researching the condition in an effort to prepare themselves for what was to come. After learning more about the disease, they discovered that scientists were looking into potential treatments that could potentially save Vallabh’s life.

With that hope in mind, they quit their jobs and eventually enrolled in a doctoral program in biological and biomedical sciences at Harvard Medical School.

In 2013, the couple founded a research organization called Prion Alliance, and used crowdsourcing to fund a study in mice that focused on using an experimental compound called antisense oligonucleotides (ASOs) they believed could potentially inhibit prion activity, which would delay the onset of the disease.

From there, they reached out to scientists with decades of knowledge and experience working with infectious prions at Rocky Mountain Laboratories.

“They were just barely getting started as graduate students,” remembered Byron Caughey, a RML senior investigator in the National Institute of Allergy and Infectious Diseases' Laboratory of Persistent Viral Diseases. “They had the vision of where they wanted to take their project, but they didn’t have the wherewithal to do the experiments that they would need. They came here to learn some of the ropes and skills they would need.”

The couple also sought one of the world’s top companies — Ionis Pharmaceuticals — that manufacture ASOs.

“It’s my understanding that they convinced them — maybe even begged them — to make the ASOs they would require,” Caughey said. “These are rare diseases. The company was not likely to make its investment back.”

Rocky Mountain Labs researcher Greg Raymond and his wife, Lynne, worked with the couple to develop the processes they would require to see if the ASOs would be effective in slowing the progression of the disease. Brent Race and Katie Williams were also members of RML team.

Prion diseases occur when normally harmless prion protein molecules become abnormal and gather in clusters and filaments in the body, including the brain. There currently is no treatment for the always-fatal diseases, which include Creutzfeldt-Jakob disease and bovine spongiform encephalopathy, sometimes called Mad Cow Disease.

The hope was the ASOs could be used to shut down the supply of the specific proteins prone to fold and become abnormal.

That, in itself, is a remarkable feat.

“The human body produces tens of thousands of different proteins,” Caughey said. “An ASO can target a single protein. … And the beauty of it is, from a practical point of view, the ASOs can be delivered in a single injection at the base of the spine. That allows for the ASOs to be distributed through the spinal fluid through the central nervous system.”

The lab was provided with several different ASOs to begin their research with mice. Over the course of about a year, they honed the number to two, Raymond said.

In a scientific paper recently published in “JCI Insight,” the scientists announced the experimental treatment had slowed the progression of scrapie, a degenerative central nervous disease caused by prions, in laboratory mice and had greatly extended their lives.

The study was conducted both at the Hamilton laboratory and at the Broad Institute of Cambridge, Massachusetts, where Vallabh and Minikel now work.

The scientists treated mice that were both infected with scrapie before and after being injected with the ASOs. In both cases, the treatment dramatically slowed the progression of the disease.

When the RML team first started the experiment, Raymond doubted the disease could be slowed in mice that were near the onset of showing clinical signs, but the researchers found the treatment slowed the progression of the disease. The treated mice lived 55% longer than those that were not injected with the ASOs.

“I think there is a great deal of hope here,” Raymond said. “I did not think that we could pull the mice back from the edge and get them to survive and appear normal, but that’s what happened.”

Vallabh and Minikel are using what they’ve learned and are moving forward in their quest to develop a drug for prion disease.

While it’s hard to estimate how long it will take for human trials to get underway, Caughey said the research could have far-reaching implications for more common neurological brain diseases, including Alzheimer’s, Parkinson’s disease and ALS.

Raymond retired from RML in December after 30 years of studying infectious prions. He calls the project the capstone in his career.

“The road has been interesting all along the way,” Raymond said. “We worked to discover how prions worked, and then how to diagnose them early and accurately, and now we have a key for a possible cure. There’s still plenty of work to be done.

“I think this is a story of hope,” he said. “Before we started, we didn’t have anything that could pull someone back from the brink. And now, maybe we do.”