CAMBRIDGE, Massachusetts – Sonia Vallabh watched helplessly as her 51-year-old mother rapidly declined into dementia and died. It wasn’t long before Vallabh realized she was destined for the same rare genetic fate.
Vallabh and her husband did what anyone in a similar situation would want: they decided to fight.
Armed with only their incredible intelligence and determination, they set out to conquer her destiny.
Twelve years later, researchers have taken a big step in that direction, finding a way to block the genetic signal enough to prevent the disease.
And in the process of trying to rescue Vallabh, they may end up saving many others too.
in The paper was published Thursday in the prestigious journal ScienceVallabh, her husband Eric Minikel, and their co-authors propose a way to inhibit the kind of brain disease that killed Vallabh’s mother.
The same approach should also work for diseases caused by the buildup of toxic proteins, such as Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and even Alzheimer’s. If it works as well as they think it does, it could also be useful for a variety of other diseases that can be treated by blocking 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 that we haven’t been able to do so easily before,” says Dr. Kiran Musunuru, a cardiologist and geneticist at the Perelman School of Medicine at the University of Pennsylvania, who was not involved in the study. Perspectives accompanying the paper.
So far, this has only been demonstrated in mice.
“The data is good right now,” Barab 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 there, but after her mother’s death, she and Minikel, then a transportation planner, both earned biology degrees. They now work together at the Broad.
“This is far from being a drug,” Vallabh said. “There is always, always reason to be careful. The sad thing is, it’s always more likely to fail than succeed at anything.”
“But there are good reasons to be optimistic.”
A dreaded disease
The disease that killed Vallabh’s mother was Prion diseasesThese include mad cow disease, which primarily affects cattle; scrapie, which affects sheep; Creutzfeldt-Jakob diseaseThe disease kills about 350 Americans each year, most of whom die within months of first showing symptoms.
These diseases are caused when the prion protein, which is present in all normal brains, begins to misfold for some as yet unknown reason.
“Prion diseases can happen to anyone,” Vallabh said, noting that the risk to the general population is 1 in 6,000.
Prion diseases can be contagious, but a federal study earlier this year found that chronic wasting disease, which is found in deer, elk and moose, is The risk of human infection is very low People who eat the meat of diseased animals.
In Vallabh’s case, the cause is genetic: After his mother’s death, he discovered he carried the same mutated gene that caused her disease, meaning he would definitely develop it.
The only question is, when?
“Age of onset is extremely unpredictable,” Vallabh said. “Age of onset in parents doesn’t really predict anything.”
How gene-editing tools work
Dr. Vallabh and Dr. Minikel reached out to colleagues at the Whitehead Institute, a biomedical research institute next door to the Broad Institute, to collaborate on a new gene-editing approach to erase the gene that caused Dr. Vallabh’s disease. The technique, developed by Whitehead scientists, is called CHARM, or histone end-binding methyltransferase autoinhibitory release.
While previous gene-editing tools have been described as like scissors or an eraser, Musnuru calls CHARM a volume control, allowing scientists to tweak genes. He says CHARM has three advantages over previous methods:
The device is small enough to fit easily inside the virus needed to deliver it: other gene-editing tools, such as CRISPR, are larger, meaning they need to be broken down into smaller pieces, requiring more viruses to deliver the pieces to the brain and risk triggering a dangerous immune response.
Musnuru said CHARM is “easily delivered to difficult-to-reach sites, such as the brain.”
At least in mice, the gene is brain-wide and appears to make desirable genetic changes without causing undesirable ones, Musnuru said.
Finally, the team found a way to turn off the gene-editing effect after it has kicked in. “If the gene-editing effect remains, it could potentially have a negative effect on the gene,” Musnuru said.
A shot on goal
While Vallabh and other researchers continue to perfect their techniques, the clock is ticking for them.
There is currently no effective treatment, and if it takes too long to develop one, Vallabh would miss his chance: Once the disease starts progressing like a runaway train, it will be much harder to stop it than if we could just block the gene from the start.
The more prion protein there is in the brain, the more likely it is to misfold — and the more likely it is that disease can spread — a process that takes the protein’s natural form and converts it into a toxic one.
That’s why it makes sense to remove as many as possible, said Jonathan Weissman, lead author of the study and director of the Whitehead lab.
“The biology is really clear. The need (for a treatment) is very real,” Weissman said.
Every cell in the brain contains the gene that makes the prion protein. Weissman believes that silencing just 50% of these genes could prevent the disease. In mice, CHARM silenced up to 80% to 90% of the genes.
“We know what we’re going to offer, now we have to figure out how to offer it,” he said.
Ben Deverman of the Broad Institute, one of the study’s co-authors, said: Published research Late last year, he showed he could deliver a virus for gene therapy throughout the brain, and other researchers are developing other viral delivery systems.
Now Vallabh and Minikel are collaborating to develop so-called antisense oligonucleotides (ASOs) that spread the risk and use a different pathway to block genes from making the prion protein.
ASOs are being tested in early stages on humans by Ionis Pharmaceuticals, but unlike gene therapy, they require regular treatment rather than a one-time procedure. The trial had to be suspended In April, the number of people wanting to volunteer exceeded the available positions, so applications were closed.
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Vallabh himself is not yet ready to start treatment.
“She only has one chance to score,” Musunuru said. “At some point, she’s going to have to decide what the best strategy is.”
Meanwhile, the clock, invisible to Vallabh, continues to tick towards the beginning.
She and Minikel are busy researching with their daughter, almost 7, and son, 4, both of whom were born through IVF and preimplantation genetic testing to ensure they wouldn’t inherit her genetic curse. (They’re incredibly lucky, Vallabh says, because they live in Massachusetts, where IVF is at least financially “affordable.”)
“We still have a mountain to climb,” Vallabh said of the road to developing a treatment. “There are still many hurdles to overcome and many things to sort out.”
Karen Weintraub can be reached at kweintraub@usatoday.com.
