CAMBRIDGE, Mass. ‒ Sonia Vallabh watched helplessly as her 51-year-old mother rapidly descended into dementia and died. It didn’t take long for Vallabh to realize she was doomed to the same rare genetic fate.
Vallabh and her husband did what anyone would want to do in their situation: they decided to fight.
Armed with incredible intelligence and determination, they set out to conquer his destiny.
A dozen years later, they took a major step in that direction, finding a way to cut off enough genetic signals to delay the disease.
And in trying to save Vallabh, they might also save many, many others.
In a paper published Thursday in the prestigious journal Science, Vallabh and her husband, Eric Minikel, and their co-authors propose a way to disrupt brain diseases like the one that killed her mother.
The same approach should also work against diseases like Huntington’s, Parkinson’s, ALS, and even Alzheimer’s, which result from the accumulation of toxic proteins. If it works as well as is thought, it could also be useful against a wide range of other diseases that can be treated by turning off genes.
“It doesn’t have to be the brain. It could be the muscles. It could be the kidneys. It could be anywhere in the body where we haven’t been able to do these things easily before,” said Dr. Kiran Musunuru, a cardiologist and geneticist at the Perelman School of Medicine at the University of Pennsylvania, who was not involved in the research but wrote a perspective accompanying the paper.
So far, they have only proven it in mice.
“The data are good overall,” Vallabh said this week from her office at the Broad Institute of Harvard and MIT, where she has worked since earning her doctorate at Harvard. She had already earned a law degree at the university, but she and Minikel, then a transportation planner, both pursued biology degrees after her mother died. Today, they work together at the Broad.
“We are far from being a drug,” Vallabh said. “There are always reasons to be cautious. Unfortunately, everything is always more likely to fail than to succeed.
“But there are good reasons to be optimistic.”
A terrible illness
The disease that killed Vallabh’s mother was part of a group of diseases called prion diseases. These include mad cow disease, which primarily affects cattle; scrapie, which affects sheep; and Creutzfeldt-Jakob disease, which kills about 350 Americans a year, most within months of the first symptoms.
These diseases are triggered when the prion protein found in all normal brains begins to misfold for an as yet unknown reason.
“Prion disease can strike anyone,” Vallabh said, noting the 1 in 6,000 risk for the general population.
Although prion diseases are, in some cases, contagious, a federal study earlier this year concluded that chronic wasting disease, found in deer, elk and moose, is highly unlikely to be transmitted to people who eat meat from diseased animals.
In Vallabh’s case, the cause is genetic. Vallabh discovered after her mother’s death that she carried the same variant of the gene that caused her mother’s disease, meaning she will almost certainly develop it.
The only question is when.
“The age of onset of the disease is extremely unpredictable,” Vallabh said. “The age of onset of the disease in your parents does not predict anything.”
How the gene editing tool works
Vallabh and Minikel reached out to colleagues at the Whitehead Institute, a biomedical research institute next door to the Broad. They asked to collaborate on a new gene-editing approach to disable the Vallabh disease gene. The technique the Whitehead scientists developed is called CHARM (for Coupled Histone tail Autoinhibition Release of Methyltransferase).
While previous gene editing tools were described as scissors or erasers, Musunuru described CHARM as a volume control, allowing scientists to adjust a gene up or down. It has three advantages over previous strategies, he said.
The device is tiny, so it easily fits into the virus needed to deliver it. Other gene-editing tools, like CRISPR, are larger, which means they have to be pieced together and a much larger amount of virus is needed to deliver those pieces to the brain, potentially causing a dangerous immune reaction.
CHARM, Musunuru said, is “easier to transmit in hard-to-transmit spaces like the brain.”
In mice at least, the virus also appears to have reached the entire brain, causing the desired genetic change without other unwanted changes, Musunuru said.
And finally, the research team found a way to turn off the gene editor once its work was done. “If it persists, there is a risk of genetic harm,” Musunuru said.
A shot on goal
While researchers, including Vallabh, continue to work to perfect an approach, time is running out for Vallabh and others.
There is no viable treatment yet, and if it takes too long to develop one, Vallabh will miss his chance. Once the disease is running like a runaway train, it will be much harder to stop than simply disabling the gene in the first place.
The more prion protein there is in the brain, the more likely it is to misfold. And the more likely it is that the disease will spread, a process that co-opts the natural form of the protein and converts it to the toxic form.
That’s why it makes sense to get rid of as much of it as possible, said Jonathan Weissman, the study’s lead author, who runs Whitehead’s lab.
“The biology is very clear. The need (for a cure) is absolutely compelling,” Weissman said.
Every cell in the brain has the gene that produces the prion protein. By silencing 50% of these genes, Weissman believes he can prevent the disease. In mice, CHARM silenced 80 to 90% of them.
“We have determined what we need to deliver. Now we need to determine how to deliver it,” he said.
Ben Deverman, a co-author of the study, published a study late last year showing that it was possible to deliver a virus carrying gene therapy into the brain. Other researchers are currently developing other virus delivery systems.
And Vallabh and Minikel hedged their bets, helping to develop what’s called an antisense oligonucleotide, or ASO, which uses another pathway to stop the gene from making the prion protein.
ASO, whose initial trials are being conducted by a company called Ionis Pharmaceuticals, requires regular treatment rather than one-time gene therapy. Recruitment for this trial had to be suspended in April because the number of potential volunteers exceeded the number of places available.
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Vallabh is not yet ready to begin treatment herself.
“She has a shot on goal,” Musunuru said. “At some point she will have to decide what the best strategy is.”
Meanwhile, the clock that Vallabh cannot see continues to tick towards the beginning.
She and Minikel are extremely busy in their research with their almost 7-year-old daughter and 4-year-old son, both born through IVF and preimplantation genetic testing to ensure they would not inherit her genetic curse. (They were very lucky, Vallabh notes, to live in Massachusetts where IVF is at least financially “affordable.”)
“There’s a mountain ahead of us,” Vallabh said of the road to recovery. “There’s still a lot of hurdles to overcome, there’s still a lot of things to resolve.”
Karen Weintraub can be reached at kweintraub@usatoday.com.