Scientists using an experimental treatment have slowed the progression of scrapie, a degenerative central nervous disease caused by prions, in laboratory mice and greatly extended the rodents’ lives, according to a new report in JCI Insight.
Dr. Byron Caughey, a senior investigator in NIAID’s Laboratory of Persistent Viral Diseases, said that Dr. Greg Raymond’s group of about twenty co-operating scientists, several working at Rocky Mountain Laboratory in Hamilton, have developed “the first late-stage treatment for prion disease that is plausibly applicable in humans.” He called the experimental results “very encouraging.”
Scientists at RML have been researching prion diseases for over 70 years. Raymond, himself, has worked at it for about thirty years. The hope, of course, has always been that some kind of treatment or cure may be developed. Although humans are not susceptible to catching scrapie, some of the other prion diseases involving mis-folded proteins can and do infect humans and to date are thought to be always fatal. While some prion diseases, like Chronic Traumatic Encephalopathy (concussions) are caused by injury, some forms of prion disease arise spontaneously, like one variant of Creutzfeldt-Jakob Disease (CJD), and some are passed on genetically, like Fatal Familial Insomnia.
The first huge hurdle in trying to understand the prion diseases turned out to be simply diagnosing the diseases in the first place. According to Caughey, there are over 10,000 different proteins found in the human brain. About thirty different diseases have been identified as involving the mis-folding of one kind of protein or another. To diagnose the disease, you need to know which protein is involved. Up until recently, the only way to find that out was to do an autopsy on the patient after death.
It took a few decades, but researchers at the lab have in the last several years perfected a diagnostic tool that is ultra-sensitive and extremely accurate. The newly developed test can be done on a living patient by taking a spinal tap and examining the patient’s spinal fluid.
Raymond said that accurately diagnosing the disease in living patients was a critical step that took a long time, but what was really needed now was some sort of treatment.
“You need to know what the disease is before you can treat it,” said Raymond. “But in this case, all the doctors could do was say, ‘we know what you’ve got now, but there’s nothing we can do about it’.” Since most of these prion diseases are extremely well developed before any clinical symptoms show up, most patients are already nearing the end of their lives by the time they realize they are sick.
In some cases, however, a patient may be diagnosed long before the infection actually develops. In the case of inheritable prion diseases, a person may be identified as carrying a gene that will most likely lead to the development of the disease at some time in their life, though the exact time of onset is unpredictable.
This was the case for Sonia Vallabh, who discovered that she has inherited a gene related to an extremely rare genetic disease that causes progressively worsening sleeplessness, called fatal familial insomnia (FFI). Difficulty sleeping soon turns into total insomnia, causing rapid physical and mental deterioration and, inevitably, death—within a year, usually sooner.
About eight years ago Vallabh watched her mother die of FFI. (You can read a story about it by Amir Schwartz published in the ‘The Atlantic’ magazine in 2015.) In the beginning the symptoms were vague, including things like speech disturbances, memory problems and small errors of judgment. But within a few months she was unable to walk or feed herself. She had become deeply paranoid and fell into a profound dementia. She went on life support and died a few weeks later.
Her death remained a mystery for several months until a piece of tissue taken from her brain tested positive for a mutation in a gene called PRNP that is known to cause FFI. Results from an autopsy had also concluded that FFI was a possible cause of death.
Children of a parent with FFI have a one in two chance of inheriting the mutated PRNP gene. Vallabh was screened for the gene and was found to have it. She will almost certainly develop and die from FFI unless treatments are developed to slow or cure the disease soon. Her mother died at age 52. The average age for onset of FFI is 50. Vallabh is in her 30s.
Apparently Vallabh was not going to just sit around and wait to see what happened. A Harvard-educated lawyer, she began attending classes at the Massachusetts Institute of Technology to learn all she could about the disease. Soon, she quit her job and took a job as a lab technician at the Massachusetts General Hospital’s Center for Human Genetic Research. Her husband, an MIT-educated urban planner, soon followed suit.
In the course of their new work and studies the couple founded the Prion Alliance, a research organization, and used crowd sourced funding to pursue the search for a cure. They also began visiting prion research laboratories like RML and the University Hospital of Zurich in Switzerland.
About five years ago, Raymond and his wife, Lynne, and other RML researchers including Brent Race and Kate Williams, and over a dozen other scientists designed an experiment on mice that could “maybe, just maybe…” as Raymond put it, lead to a treatment for humans.
The idea was to test out a group of compounds, called Antisense oligonucleotides (ASOs), that had shown some indication of being able to inhibit protein production in the brain. The proteins involved in these prion diseases are in the body naturally performing different functions. Some misfolding of the proteins always occurs, according to Caughey. But normally the brain has a mechanism for dealing with the clumps of misfolded proteins that can form sort of a “garbage disposal” mechanism. But at some point, the garbage disposal system, for whatever reason, perhaps just aging, can’t keep up with the garbage being produced and the accumulation of clumps of mis-folded proteins spirals out of control.
The idea to be tested was whether reducing the amount of normal protein production could reduce the accumulation of trash and possibly give the garbage disposal system a chance to do its job. It took a lot of time to develop the right ASO that would reduce the production of a single kind of protein and not interfere with other protein production or have any other unrelated effects.
Caughey said the hope was that maybe by turning down the number of proteins that are being produced it could give the garbage disposal mechanism a chance to catch up on things and possibly even recover.
The study group approached a company, Ionis Pharmaceuticals, which was producing AOS and asked for help.
“These ASO compounds are very specifically designed and this company is the best. This is a rare disease, so they aren’t going to be using a lot of this drug. I think they are doing this out of the goodness of their heart,” said Caughey.
“But what Greg [Raymond] has shown has never been seen before,” said Caughey. What he showed was that with one dose of the proper AOS, even at the stage of progression at which symptoms are beginning to show, the lifespan of the mouse could be extended significantly.
Raymond called the results of the experiment “amazing.” Because the mice were directly infected by injection to the brain, the researchers knew how long it would take for the mice to show signs of illness and pretty much when they would die.
Two different ASOs were tested and the mice treated with both lived longer than untreated mice, by 61% (274 days versus 170 days) and 76% (300 days versus 170 days), respectively. The RML group also tested the ASOs against established prion disease, treating mice 17 weeks after they were infected with scrapie – near the onset of clinical signs. Mice treated with ASO1 did not show signs of clinical disease for a median 189 days, or 33% longer than untreated mice (142 days). They also showed slower disease progression and lived 55% longer than untreated mice (244 days versus 157 days). ASO2 had no beneficial effect.
Raymond said, “We’ve shown that using the right ASO in infected mice can slow down the disease and extend their lifespan by 55%,” said Raymond. “It means we maybe, just maybe, can develop a treatment for humans.”
It will take time. A new ASO will have to be developed to work specifically on humans and that work, he said, has already begun.
“We are not here to cure mice of prion disease,” said Raymond. “We are looking to cure humans.”
He said the successful proof of concept was so clean that Vallabh and her husband, along with Ionis and the Broad Institute, are already working with the Food and Drug Administration to begin human trials.
Caughey said that, given the nature of the disease, the terrible suffering on the part of the patient and family and the inevitable end without treatment, the FDA would probably be willing to expedite the human trials, since treatment shows the potential of helping even in the late stages of the disease. If not a cure, it may at least extend the patient’s lifespan and the quality of life in those with the disease.
If the concept works in humans for the rarest of prion diseases, it may well work for more widely spread prion diseases like Alzheimer’s and Parkinson’s. Alzheimer’s currently affects about 5 million people in the U.S. and experts predict that by 2050 that number will have risen to 15 million. Parkinson’s infects about a quarter as many.
Other researchers have seen promising initial results in humans with ASOs directed against Alzheimer’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and Huntington’s disease.