Ben Prosser had devoted more than a decade of his scientific career to the problem of heart failure, bringing valuable new knowledge to a disease that affects millions of people. Then, in August 2018, life gave him a rare medical puzzle he couldn’t solve: his baby girl, Lucy.
Several times a day, erratic signals flooded the little girl’s brain, causing her to twitch involuntarily and sometimes scream in pain – a type of seizures called infantile spasms. Genetic testing revealed the cause: she was born with a rare mutation that meant she could never walk or talk.
What insight could a heart specialist at the University of Pennsylvania offer on a brain disorder?
More than four years later, the answer turns out to be: a lot. Within weeks of the diagnosis, Prosser teamed up with two prominent neighboring scientists at Children’s Hospital of Philadelphia and began to refocus his lab on neurodevelopmental diseases like his daughter’s. In February, an anonymous donor gave them $25 million, potentially allowing the group to start testing treatments in children in as little as two years.
Prosser, an associate professor of physiology at Penn’s Perelman School of Medicine, is cautious about the chances of success. Yet the landscape for tackling rare diseases has changed dramatically in recent years – with the discovery of hundreds of new disease-causing mutations and the emergence of genetic therapies to put this knowledge into practice.
And Lucy’s rare disease, which affects 1 in 30,000 children, would benefit from a rare stroke of luck: against all odds, her father was able to do something about it.
But first, he had to learn what was making her sick.
READ MORE: Childhood epilepsies were once a medical mystery. Now, several types of treatments are showing promise.
What caused the seizures
Lucy’s disorder was so rare that it had no proper name, just an alphabet soup designation: STXBP1 encephalopathy. His father had never heard of it.
In an effort to make sense of his daughter’s complex condition, Prosser sought refuge the only way he knew how: by reading the scientific literature. Surely many researchers were to study it, and would anyone be working on a promising therapy?
He found almost nothing. But in one of the few studies he found — published just two years before Lucy was born — Prosser saw that one of the authors was CHOP neurologist Ingo Helbig.
Just two weeks later, Prosser was in a room with Helbig and his colleague Beverly L. Davidson, an expert in the rapidly evolving field of gene therapy, strategizing on a whiteboard.
“It’s Ben’s superpower,” said his wife, Erin, a marketing manager. “Bring people together.”
They explained to him how the STXBP1 gene carried the recipe for the human body to make a crucial protein, allowing brain cells to communicate with each other. But the slightest glitch in this recipe could cause epileptic seizures and neurological developmental delays.
Such a mutation was the equivalent of typing a letter wrong. If you imagine the correct recipe as a sentence – say, “The cat ran down the street”, the mutated version became “The rug ran down the street”. In other children, the mutation looked like a molecular stop sign, causing the brain to stop reading the recipe halfway through: “The cat ran.”
In Lucy’s case, her father learned, the mutation prevented her brain cells from putting the pieces of the sentence together into a finished product. The words were there – cat, ran, down, Street – but they ended up on the floor of the editing room.
The ketogenic diet
As the three scientists began to explore possible solutions, the crises continued. Lucy was in and out of the hospital for months as her doctors unsuccessfully tried one anti-epileptic drug and then another.
Her mother carefully recorded each episode in a diary – the date, time, duration – and took videos with her phone. These weren’t dramatic convulsions, but a series of quick little jerks called infantile spasms. The girl’s eyes flickered to the right and her shoulders shrugged rapidly – maybe 50 times in three minutes, with half a dozen such episodes a day.
“There’s nothing you can really do,” his mother said. “You just have to count, hold his hand and tell him that everything is fine.”
In mid-November 2018, the Prossers tried a new approach: an extreme version of the popular ketogenic diet.
When Adults Try Various Low-Carb Foods keto diets for weight loss typically aim to get two-thirds of their calories from fat. But to control Lucy’s seizures, nutritionists told the Prossers she should get 90% fat. Smashed avocados with mayonnaise. Greek yogurt mixed with grapeseed oil.
“Everything is measured to the nearest tenth of a gram,” Ben Prosser said.
Doctors don’t fully understand why the diet may help some children with epilepsy, but by forcing brain cells to burn fat instead of carbohydrate sugars, it appears to reshape metabolism in a way that calms an overactive brain, Prosser said.
The diet does not work for everyone. But after a month and a half of dieting, on December 29, Lucy went a full day without seizures. Then a second day, and a third.
Lucy hasn’t had a seizure for over four years.
Find a treatment
While once Lucy seemed disengaged and unresponsive, she began to pay close attention to her surroundings, lighting up the room with a smile when she saw her parents or her older brother, Sam, who is two years older. .
“I didn’t know if she was ever going to find out that I’m her mom,” Erin Prosser said. “Now she knows we are her people.”
Yet the seizures were only a symptom of Lucy’s underlying disorder. Her brain cells still couldn’t communicate well with each other, meaning she would have trouble with all of life’s basic skills: learning, problem solving, walking and speaking.
Prosser and the CHOP scientists continued to work on a multi-pronged strategy, which they had sketched out on the first day on the whiteboard.
The key was that in Lucy and other children with her disorder, the mutations occur in only one of their two copies of the STXBP1 gene. The other is fine, meaning their brain is making half of the key protein they need.
One option was gene therapy, replacing the faulty copy of the gene with a normal copy. The first such treatment had been approved by the FDA the previous year, based on research at CHOP, for the treatment of a rare form of blindness.
Another possibility was an emerging genetic technique called ASO, which they could use to maximize the yield of his “good” recipe while leaving the other only imperfect.
But the STXBP1 protein is difficult to study. It’s only found in the brain, so doctors can’t measure it with a simple blood test.
For this, Ben Prosser had to make copies of his daughter’s brain cells in a laboratory.
Create stem cells
Prosser took blood samples from Lucy and her own arm and sent them to a CHOP lab. Scientists have reprogrammed their blood cells there into blank slates: stem cells. These induced stem cells were then converted back into brain cells – some of them exact copies of Lucy’s and some of her father’s.
When he tested copies of his own brain cells, Prosser found that they produced normal levels of the key protein. Lucy only won half of it.
But then, using a gene-editing technique called CRISPR, Prosser was able to fix the faulty copy of Lucy’s gene. His cells were then able to make enough protein.
With the results, and other pilot experiments in mice, Prosser and his partners began winning small grants. One was from a family of a patient with a similar disorder. Another came from the American Epilepsy Society, then the National Institutes of Health.
In February came the big prize – $25 million, for a joint Penn and CHOP center that will study Lucy’s condition and related disorders.
In a world where everyone affected by a rare disease is looking for funds and attention, the parents of other children with these diseases can hardly believe their luck. Prosser is now a member of the scientific advisory board of a support group called the STXBP1 Foundation, which has also contributed research funds. And unexpectedly, another scientist, Michael Boland, a cell biologist at Columbia University, has a son with Lucy’s disease, and he also sits on the board.
The future
Lucy was sitting on the floor of the Prossers’ living room one day in February, throwing her arms in the air expectantly.
“Do you want to go step by step?” his father asked.
Taking her hands in his, Prosser gently got her to her feet, and she managed to take a few stiff steps before falling to the ground.
More than four years after the diagnosis, Lucy is in regular therapy, attends a special school, and is now on a less extreme version of the keto diet. She can say “dad” and say the word “mom”, although no sound comes out. Developmentally, she is the equivalent of a 1-year-old child.
As a parent, worried that each passing month represents a dwindling opportunity to make a difference in Lucy’s development, Prosser wishes he could give her cutting-edge medication immediately. As a scientist, he’s more cautious about predicting when he and his partners might develop a cure, but he’s feeling increasingly optimistic.
“I used to say five years,” he said. “It’s shorter than that now.”
Davidson, a gene therapy specialist at CHOP, said it could be possible to test treatments in as little as two years. It could be gene therapy, ASO, or maybe an existing drug that was designed for other purposes.
“We take as many shots on goal as possible,” she said.
Among Lucy’s many roots is big brother Sam, now 6 years old. On January 1, he announced to the family that he had made his sister the subject of a special New Year’s wish.
“She’s going to walk and talk and know things,” he said.
With enough shots on goal, maybe one day soon, she will.