Maggie Hoyle-Germann woke with a start, her phone pinging beside her bed. She hadn’t slept well, all these nightmares about losing Lincoln. And now, before dawn, text messages were streaming in.
She swallowed a Xanax, then picked up her cell phone.
“Did you hear?”
“Can you believe it?”
“Was it Lincoln?”
The day before, in a pediatric room at the UCLA Medical Center, a 9-month-old boy had gotten the first injection of gene therapy — the shot her son had been waiting for.
Lincoln was almost 4 now, older than boys with his fatal muscular disease were expected to live. He had been enrolled in a clinical trial for patients with X-linked myotubular myopathy for more than a year. Now, in September 2017, actual dosing had finally begun.
“Now we can start the countdown!” Jamie’s mom, Angelica Santiago-Townshend, cheered into Maggie’s phone that day.
Together, they did the math: Doctors were going to wait four weeks after the first dose to do the second, to make sure nothing went wrong.
That meant boy #2 would be in late October; boy #3 at the end of November …
“If it causes kidney or heart failure,” Angelica said, “they might wait even longer.”
“We can’t afford to wait much longer,” Maggie said.
Days later, in a glass-walled office overlooking San Francisco Bay, Matt Patterson was still anxious, hoping to hear how the UCLA boy was doing.
“It’s incredibly exciting,” Patterson said. “It’s the milestone we’ve all been striving for.”
After the first boy had been treated, the staff at his biotech company had gone out for drinks and toasted to his future. As far as they knew, nothing had gone wrong.
“But I won’t feel like I accomplished something until I see these kids improve,” Patterson said.
His own son was only a few months old and healthy. But now that he was a father, his mission felt more personal. Scientists at his company weren’t trying to ease pain or provide therapy. They didn’t see their product as a treatment. They wanted to save these boys.
They called it a rescue.
Patterson had studied biochemistry and worked at Genzyme Corp., BioMarin Pharmaceutical and Amicus Therapeutics trying to get new drugs to market. One of his college friends had a daughter with a rare, terminal illness, so much of Patterson’s work focused on finding cures for “orphan” diseases.
He didn’t know much about gene therapy — or X-linked myotubular myopathy — until he met Barry Byrne from the University of Florida. Byrne was trying to repair broken genes that caused muscular diseases. Through Byrne, Patterson met the Seattle scientist who had saved the dying puppies and other researchers across the country.
For most of 2012, Patterson tried to convince the venture capital firm he was consulting for to help him start a company. Eventually, they gave him $1 million. He formed Audentes Therapeutics that fall, naming his company after a Latin word for “courage, boldness, daring.”
For the next six months, he holed up in his Manhattan kitchen, calling would-be investors, explaining gene therapy — and trying to assure them that yes, soon, the government would allow doctors to correct human DNA.
If scientists in his lab could produce the corrected version of the MTM1 gene, Patterson thought, he could buy the means to deliver it. The French researchers who had infected the mice had been using AAV8 — an adeno-associated virus — that doesn’t cause diseases or side effects. Researchers insert the correct DNA into a shell of the virus, then inject that into the patient. The “vector” delivers the new gene, which overrides the broken one.
But in 2015, Patterson learned that the French group couldn’t make enough of those vectors to take to a clinical trial. He would have to build his own manufacturing facility. It took almost two years to construct the 38,000-square-foot building.
By the time the first boy got the infusion, that fall of 2017, Patterson had raised $300 million, taken his company public, hired 150 employees, produced and tested gene therapy — and convinced the FDA to approve a clinical trial.
If the first dose for X-linked myotubular myopathy went to market, he hoped, the process they were creating could be used to deliver gene therapy to cure a host of other genetic diseases.
Along the office halls, portraits of boys with fatal diseases reminded everyone who they were working for.
In his office on the 17th floor, John Gray keeps a windsurfing board and a jar of jelly beans. He oversees research for Audentes and studied gene therapy for decades at Harvard and St. Jude Children’s Hospital, working to treat diseases from diabetes to dwarfism. Much of his research focuses on improving vectors to deliver a correct version of a broken gene.
When Patterson recruited him, he asked what Gray wanted to accomplish in the later part of his career: Keep researching? Or work for a company that could bring a cure to market?
“I feel like a kid in a candy store,” Gray said. “Every time I hear of a new disease, I think: ‘Oh, we can solve this.’”
It took 40 years, he said, to go from understanding the basic structure of DNA to getting government approval for the first gene therapy, in 1990.
Nine years later, Jesse Gelsinger’s death halted gene therapy in the United States for nearly two decades. The virus that delivered the new DNA to the Arizona teenager triggered a severe reaction from his immune system, which shut down his organs.
Scientists still don’t fully understand why that early vector caused such a reaction, Gray said. But newer ones are much less likely to create problems.
“I think we’re going to have a great track record,” he said. “But it takes a long time to know what the long-term effects will be.”
Doctors need to treat children as early as possible, to be able to rehabilitate them as fully as possible, said Suyash Prasad, Audentes’ chief medical officer. He joined Patterson’s team in 2014, after working for BioMarin, Genzyme Corp. and Eli Lilly studying treatments for rare pediatric disorders.
Because myotubular myopathy isn’t progressive, Prasad said, affected boys don’t lose muscle over the years. So there’s hope that, with the corrected gene, their muscular and respiratory functions could fully recover.
But as the boys age, their bodies begin to break down, causing other problems with bones and organs, complications gene therapy might not be able to fix.
“I don’t think there will be much difference between treating boys age 0 and 4,” Prasad said. “But for older children, there’s a possibility recovery won’t be as full.”
There would be three levels of serum used in the clinical trial, he explained: The first three boys would get a low dose, the next three a medium, the final cohort would get the highest concentration. If the low dose is effective enough, the doctor said, they might not need to increase the intensity.
“We have every hope of succeeding,” he said. “But we actually don’t know if it will work at all.”
The rescue is made in a laboratory, inside a long, cream-colored warehouse, about 10 miles south of Audentes’ downtown office. The building includes research areas, freezers and rows of vats to grow cells.
To keep everything sterile, workers don paper bonnets, white lab coats, blue booties and goggles.
The serum — AT132 — starts with a vial of frozen cells: Human embryonic kidney cells, offspring of samples first collected in the 1970s, grown in laboratories ever since.
When the cells thaw, workers put them into a liquid culture where they begin to divide. Then they separate the cells and move them into increasingly larger containers.
In 14 days, one milliliter of cells becomes 10 million.
Scientists transfer the cells into two large, spinning fermentation chambers called bioreactors, then add the new gene. As the cells spin, the virus incorporates the gene. “Like candy coating that carries the correct DNA,” one scientist said.
Agitators in the 500-liter bioreactors keep the viscous liquid turning. Filters sift out cell particles and proteins. Through a window, the purified serum looks like frothy, pink beer.
It takes about a month to make the treatment. The final product is clear, kept frozen on liquid nitrogen, shipped to hospitals at 110 degrees below zero.
The vial that carries the 10-milliliter dose of serum is about as big as a thumb. No one will say what it might sell for, but one analyst predicts the treatment could cost up to $5 million for a single dose.
Keeping a boy like Lincoln alive costs Medicaid at least $1.5 million a year, funding supplies, hospitalizations, round-the-clock nursing care. So scientists — and parents — are hoping insurance will cover the bill, seeing how much a treatment would save over time.
The rescue itself is simple: A doctor inserts an IV into the boy’s arm, and for a couple of hours, the liquid drips into his vein. The boys can be awake during the infusion, and as long as they don’t show any side effects, they can go home that night.
If this treatment — and the new vector — are effective and safe, the Food and Drug Administration could allow companies to start marketing gene therapy for all kinds of disorders. In a few years, what was once unimaginable might become as routine as getting a vaccination for polio.
A few weeks later, Maggie and her husband, Anthony DeLuna, loaded Lincoln and all his machines into the car, then drove three hours to Gainesville. As part of the clinical trial, they had to travel to the University of Florida four times a year, so doctors could test Lincoln’s breathing, measure his mobility, take X-rays, draw blood.
Maggie and Anthony had been making the pilgrimage for 18 months, but still had no idea when their son would get his shot.
“You can wait in here,” said Dr. Barbara Smith, ushering them into her office. Katie Germann came, too, pushing her nephew’s stroller. Smith closed the door.
She had known Lincoln since he was months old, followed his progress for years. Now, she wanted to bring in her colleague.
Byrne had been among the earliest scientists to work with AAV8 vectors and had collaborated with researchers around the world. That month, he had 50 children enrolled in various clinical trials.
“He has some papers for you to sign,” said Smith, pushing a pile toward Maggie.
Maggie flipped through 23 pages: Consent forms for the clinical trial.
She showed them to Anthony, then stared at the doctor. “Does this mean it’s official?” she asked. “Here, give me a pen. I don’t care what it says. We’ll sign it.”
Lincoln would be the fourth boy to get the treatment, Smith told them.
Maggie and Katie fell into each other’s arms, sobbing. Anthony lifted his glasses and wiped his eyes.
Finally, they had a date: Nov. 6. Just three weeks away. A month before Lincoln would turn 4.
“This work we’re doing, we don’t know how long it will last,” Byrne told them. “Lincoln could improve, then decline again.”
The dogs, by then, were 5 years old — and still seemed great. But no one knew if the improvements would fade or wear off entirely.
Or if, down the road, scientists could give another dose to dogs or boys.
Maggie was stunned. She’d thought the fix was forever. Later, she told Anthony, “But even if it’s only for a while … Medicine is advancing at such a rapid pace. Look at all the things that have happened just this year. There’s no way Lincoln wouldn’t get into a redosing study if he needed it down the road. This is some science-fiction stuff.”
During the drive home, Maggie’s phone rang. Angelica told her that Jamie also had gotten his date: Nov. 1. “This is just terrifying,” Angelica said. “No one really knows what’s going to happen.”
Maggie and Anthony were scared, too, but couldn’t stop smiling. Anthony said it was like winning the golden ticket to Willy Wonka’s Chocolate Factory. Maggie felt like Moses had just tapped them to cross into the promised land.
The next night, after settling back in at home, their favorite nurse brought them lottery tickets. Maggie dressed Lincoln in his Captain America T-shirt, and Anthony opened three Yuenglings.
“To your family!” said the nurse, raising his beer above Lincoln’s bed.
“To the next dose!” said Maggie.
“To Lincoln!” said Anthony, bending over his boy. “Give me a high-five!” Lincoln did.
“Alexa!” Anthony shouted. “Play Celebration! Volume 10!”
He wrapped his arms around Maggie and started dancing, making up new words to the old song: “Ge-ene ther-a-py! C’mon!”
Senior news researcher Caryn Baird contributed to this story.