After her mother dies of dementia, a medical researcher searches for a cure

CAMBRIDGE, Massachusetts — Sonia Vallabh watched helplessly as her 51-year-old mother rapidly declined from dementia and died. It didn’t take long for Vallabh to realize she was facing the same rare genetic fate.

Vallabh and her husband did what anyone in their situation would do: they decided to fight.

Armed with little more than incredible intellect and determination, they set out to master their destiny.

Twelve years later, they have taken a significant step in this direction and found a way to switch off enough genetic signals to stop the disease.

And while they try to save Vallabh, they may also save many, many others.

In a paper published Thursday in the prestigious journal Science, Vallabh, her husband Eric Minikel, and their co-authors propose a way to put an end to brain diseases like the one that killed their mother.

The same approach should also work against diseases like Huntington’s, Parkinson’s, ALS and even Alzheimer’s, which arise from the accumulation of toxic proteins. If it works as well as thought, it could also be useful against a variety of other diseases that can be treated by silencing genes.

“It doesn’t necessarily have to be the brain. It could be the muscles. It could be the kidneys. It could really be anywhere in the body where we haven’t been able to do these things so easily before,” said Dr. Kiran Musunuru, a cardiologist and geneticist at the University of Pennsylvania’s Perelman School of Medicine who was not involved in the research but wrote an accompanying viewpoint to the article.

So far they have only been able to prove this in mice.

“The data are good so far,” Vallabh said this week from her office at the Broad Institute of Harvard and MIT, where she has worked since completing her PhD at Harvard. She already had a law degree from the university, but she and Minikel, then a transportation planner, both pursued degrees in biology after their mother died. Now they work together at the Broad Institute of Harvard.

“We are far from being a drug,” Vallabh said. “There is always, always reason to be cautious. Unfortunately, it is always more likely to fail than succeed.”

“But there is legitimate reason for optimism.”

A terrible disease

The disease that killed Vallabh’s mother was part of a group of illnesses known as prion diseases, which include BSE, which primarily affects cattle, scrapie, which affects sheep, and Creutzfeldt-Jakob disease, which kills about 350 Americans each year – most within a few months of the first symptoms.

These diseases are caused by the prion protein, which is present in all normal brains, misfolding for reasons that are still unknown.

“Prion disease can affect anyone,” Vallabh said, pointing to the 1 in 6,000 risk for the general population.

Although prion diseases are contagious in some cases, a federal study conducted earlier this year concluded that the chronic wasting disease that occurs in deer, elk and moose is very unlikely to be transmitted to humans who eat the meat of sick animals.

In Vallabh’s case, the cause is genetic. After her mother died, Vallabh found out that she carries the same variant of the gene that caused her mother’s disease, which means she is sure to develop the disease as well.

The only question is when.

“The age of onset is extremely unpredictable,” Vallabh said. “The age at which your parents develop the disease doesn’t really predict anything.”

How the genome editing tool works

Vallabh, Minikel and their colleagues developed a genome editing approach they call CHARM (for Coupled Histone tail Autoinhibition Release of Methyltransferase).

While previous gene editing tools have been described as scissors or an eraser, Musunuru described CHARM as a volume control that allows scientists to tune a gene up or down. It has three advantages over previous strategies, he said.

The device is tiny, so it can easily fit inside the virus it’s designed to deliver. Other genome editing tools like 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 reaction.

CHARM, says Musunuru, is “easier to deliver to hard-to-reach areas like the brain.”

At least in the mouse, it also appears to have reached the entire brain and caused the desired genetic changes without causing other, undesirable changes, Musunuru said.

Finally, the research team found a way to turn off the gene editor once it had finished its work. “If it stays there, there is a risk that it will cause genetic damage,” Musunuru said.

A shot on goal

While researchers, including Vallabh, continue to work on perfecting an approach, the clock is ticking for Vallabh and others.

There is currently no effective treatment, and if it takes too long to develop one, Vallabh will miss her chance. Once the disease process gets going, like a runaway train, it will be much harder to stop than if you just turn off the gene in the first place.

The more prion proteins there are in the brain, the more likely they are to misfold. And the more likely the disease is to spread. In the process, the natural form of the protein is converted into the toxic form.

That’s why it makes sense to get rid of as much of it as possible, says Jonathan Weissman, the study’s lead author, who runs a lab at the Whitehead Institute, a biomedical research institute adjacent to the Broad.

“The biology is really clear. The need (for a cure) is so compelling,” Weissman said.

Every cell in the brain has the gene to make the prion protein. Weissman believes he can prevent the disease by knocking out even 50% of these genes. In mice, CHARM has been able to knock out up to 80% to 90% of these genes.

“We’ve figured out what we need to deliver. Now we need to figure out how to deliver it,” he said.

Another study co-author, Ben Deverman of the Broad Institute, published a study late last year showing he could distribute a gene therapy-delivering virus throughout the brain. Others are currently developing other virus delivery systems.

Vallabh and Minikel played it safe and helped develop a so-called antisense oligonucleotide (ASO), which uses a different pathway to prevent the gene from producing the prion protein.

The ASO, which is being tested in early human trials by a company called Ionis Pharmaceuticals, requires regular treatment rather than one-time gene therapy. Recruitment for that trial had to be paused in April because the number of potential volunteers exceeded the available places.

Personalized therapy:This life-saving treatment was developed for one person. Could it be the future of healthcare?

Vallabh himself is not yet ready to start treatment.

“She has a shot on goal,” Musunuru said. “At some point she has to decide what the best strategy is.”

Meanwhile, the clock, which Vallabh cannot see, continues to tick towards the beginning.

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