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 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 incredible intellect and determination they set out to conquer her destiny.
A dozen years later, they've taken a major step in that direction, finding a way to shut off enough genetic signals to hold off the disease.
And in the process of trying to rescue Vallabh, they may save many, many others as well.
In a paper published Thursday in the prestigious journal Science, Vallabh and her husband, Eric Minikel, and their co-authors offer a way to disrupt brain diseases like the one that killed her mother.
The same approach should also work against diseases such as Huntington's, Parkinson's, Lou Gehrig’s disease (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 vast array of other diseases that can be treated by shutting 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 have not easily been able to do these things before," said Dr. Kiran Musunuru, a cardiologist and geneticist at the University of Pennsylvania's Perelman School of Medicine, who wasn't involved in the research but wrote a perspective accompanying the paper.
So far, they've proven it only in mice.
"The data are good as far as they go," Vallabh said this week from her office at the Broad Institute of Harvard and the Massachusetts Institute of Technology, where she has worked since getting a Ph.D. at Harvard. She had already gotten 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 the Broad.
"We're far from this being a drug," Vallabh said. "There's always, always reason for caution. Sadly, everything is always more likely to fail than succeed.
"But there is justifiable reason 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 affects mostly 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 triggered when the prion protein found in all normal brains starts misfolding for some reason, as yet unknown.
"Prion disease can strike anybody," Vallabh said, noting the 1 in 6,000 risk to the general population.
Though 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 very unlikely to pass to people 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 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 actually predict anything."
How the gene-editing tool works
Vallabh and Minikel approached colleagues at the Whitehead Institute a biomedical research institute next to the Broad. They asked to collaborate on a new gene-editing approach to turn off Vallabh's disease gene. The technique developed by Whitehead scientists is calledCHARM (for Coupled Histone tail Autoinhibition Release of Methyltransferase).
While previous gene-editing tools have been described as scissors or erasers, Musunuru described CHARM as volume control, allowing scientists to tune a gene up or down. It has three advantages over previous strategies, he said.
The device is tiny, so it fits easily inside the virus needed to deliver it. Other gene-editing tools, like CRISPR, are bigger, which means they need to be broken into pieces and much more of the virus is needed to deliver those pieces to the brain, risking a dangerous immune reaction.
CHARM, Musunuru said, is "easier to deliver to hard-to-deliver spaces like the brain."
At least in the mouse, it also seems to have reached throughout the brain, making the desired genetic change without other, unwanted ones, Musunuru said.
And finally, the research team figured out a way to turn the gene editor off after its work was done. "If it's sticking around, there's the potential for genetic mischief," Musunuru said.
One shot on goal
While researchers, including Vallabh, continue to work to perfect an approach, the clock for Vallabh and others is ticking.
Right now there's 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'll be much harder to stop than it would be to just shut the gene off in the first place.
The more prion protein in the brain, the more likely it is to misfold. And the more likely it is for the disease to spread, a process that co-opts 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, the senior author of the study, who leads 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 those genes, Weissman figures he can prevent the disease. In mice, CHARM silenced up to 80% to 90%.
"We've figured out what to deliver. Now we have to figure out how to deliver it," he said.
Another of the paper's co-authors, the Broad's Ben Deverman, published a study late last year showing he could deliver a gene-therapy-carrying virus throughout the brain. Others are developing other viral delivery systems.
Vallabh and Minikel have hedged their bets, helping to develop a so-called antisense oligonucleotide, or ASO, which uses another path for stopping the gene from making the prion protein.
The ASO, which is in early trials in people by a company called Ionis Pharmaceuticals, requires regular treatment rather than the one-and-done of gene therapy. Recruitment for that trial had to be paused in April because the number of would-be volunteers outstripped the available slots.
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Vallabh isn't ready yet to start any treatment yet herself.
"She has one shot on goal," Musunuru said. "At some point, she'll have to decide what's the best strategy."
In the meantime, the clock Vallabh can't see continues to tick toward the onset.
She and Minikel stay exceedingly busy with their research along with their daughter, almost 7, and 4-year-old son ‒ both born via IVF and preimplantation genetic testing to ensure they wouldn't inherit her genetic curse. (They were super lucky, Vallabh notes, to be living in Massachusetts where IVF is at least "approachable" financially.)
"There is a mountain ahead of us," Vallabh said of the path 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.
