CAMBRIDGE, Massachusetts ‒ 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 that she was destined for 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 little more than intellect and incredible determination, they set out to conquer her destiny.
A dozen years later, they’ve taken a big step in that direction, finding a way to shut down the genetic signals enough to prevent the disease.
And in the process of trying to save Vallabh, they may save many, many others.
In an article published Thursday in the prestigious journal Science, Vallabh and her husband, Eric Minikel, and their co-authors offer a way to stop brain diseases like the one that killed her mother.
The same approach should work against diseases such as Huntington’s, Parkinson’s, ALS and even Alzheimer’s, which result from the accumulation of toxic proteins. If it works as well as they think, it could also be useful against a number 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 really anywhere in the body where we weren’t easily able to do these things before,” said Dr. Kiran Musunuru. , a cardiologist and geneticist at the University of Pennsylvania Perelman School of Medicine, who was not involved in the research but wrote a perspective accompanying the paper.
So far, they have only proven this in mice.
“The data is good as far as it goes,” Vallabh said this week from her office at the Broad Institute of Harvard and MIT, where she has worked since earning her Ph.D. at Harvard. She already had a law degree from the university, but she and Minikel, then a transportation planner, both pursued biology degrees after her mother’s death. Now, they work together at Broad.
“We are far from being a drug,” Vallabh said. “There is always, always reason for caution. Unfortunately, anything is always more likely to fail than to succeed.
“But there are justifiable reasons for optimism.”
A terrible disease
The disease that killed Vallabh’s mother was one of a group of conditions called prion diseases. These include mad cow disease, which mainly affects cattle, scrapie, which affects sheep, and Creutzfeldt-Jakob disease, which kills about 350 Americans a year — most within months of their first symptom.
These diseases are caused when the prion protein found throughout the normal brain begins to misfold for some reason, as yet unknown.
“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 the chronic damage disease, found in deer, elk and louse, is highly unlikely to be transmitted to humans who eat the meat of sick animals.
In Vallabh’s case, the cause is genetic. Vallabh discovered after her mother’s death that she carries the same variant of the same gene that caused her mother’s disease, meaning she will almost certainly develop it.
The only question is when.
“The age of onset is extremely unpredictable,” Vallabh said. “Your parent’s age of onset doesn’t predict anything.”
How the gene editing tool works
Vallabh and Minikel turned to colleagues at the Whitehead Institute, a biomedical research institute near the Broad. They sought to collaborate on a new gene-editing approach to turn off Vallabh’s disease gene. The technique developed by Whitehead scientists is called CHARM (for Release of Paired Tail Histone Methyltransferase Autoinhibition).
While previous gene-editing tools have been described as scissors or an eraser, Musunuru described CHARM as a volume control, allowing scientists to tune a gene up or down. It has three advantages over previous strategies, he said.
The device is small, so it easily fits inside the virus needed to deliver it. Other gene-editing tools, such as CRISPR, are larger, meaning they have to be broken into pieces and much more virus is needed to deliver those pieces to the brain, risking a dangerous immune response .
SHARM, Musunuru said, is “easier to deliver in hard-to-distribute spaces like the brain.”
At least in the mouse, it also appears to have reached the entire brain, making the desired genetic change without other, unwanted ones, Musunuru said.
And finally, the research team found a way to turn off the gene editor after its work is done. “If it’s hanging around, there’s potential for genetic mischief,” Musunuru said.
A shot on goal
As researchers, including Vallabh, continue to work to perfect an approach, the clock for Vallabh and others is ticking.
There is currently no viable treatment, and if it takes too long to develop one, Vallabh will miss her window. Once the disease process starts, like a runaway train, it will be much harder to stop than simply turning off the gene in the first place.
The more prion protein in the brain, the more likely it is to misfire. And the more likely the disease is to spread, a process that combines the natural form of the protein and converts it to the toxic form.
That’s why getting rid of as much of it as possible makes sense, said Jonathan Weissman, senior author on the study, who runs a Whitehead lab.
“The biology is really clear. The need (for a cure) is so compelling,” Weissman said.
Every cell in the brain has the gene for making the prion protein. By silencing even 50% of these genes, Weissman thinks it could prevent the disease. In mice, CHARM was silenced by 80% to 90%.
“We’ve figured out what to offer. Now we have to figure out how to deliver it,” he said.
Another of the paper’s co-authors, Broad’s Ben Deverman, published a study late last year showing he could deliver a virus carrying gene therapy throughout the brain. Others are developing other viral delivery systems.
And Vallabh and Minikel have hedged their bets, helping to develop a so-called antisense oligonucleotide, or ASO, which uses a different pathway to stop the gene from making the prion protein.
ASO, which is in early human trials by a company called Ionis Pharmaceuticals, requires regular treatment instead of a gene therapy. Recruitment for that trial had to be suspended in April because the number of potential volunteers exceeded the available places.
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Vallabh is not yet ready to start any treatment himself.
“She has a shot at goal,” Musunuru said. “At some point, she’s going to have to decide what the best strategy is.”
Meanwhile, the clock that Vallabh can’t see keeps ticking towards the start.
She and Minikel stay extremely busy with their research along with their daughter, almost 7, and 4-year-old son — both born through IVF and pre-implantation genetic testing to make sure they won’t inherit her genetic curse. (They were very lucky, Vallabh notes, to live in Massachusetts where IVF is at least “affordable” financially.)
“There’s a mountain ahead of us,” Vallabh said of the road to a cure. “There’s still a lot of hurdles, there’s still a lot to figure out.”
Karen Weintraub can be reached at kweintraub@usatoday.com.
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