‘Molly is a success story’: Gene therapy that improved Nebraska teen’s vision could soon be available nationwide
OMAHA, Neb. — The first new thing Molly Troxel saw was a familiar sight — some might even say an old friend — to most other people.
“I saw the moon,” she said. “I’d never seen it before.”
Then came more firsts: her dog’s eyelashes; the twinkle lights in the boutique next door to the pizza shop.
Molly, now a 15-year-old high school sophomore, was born with Leber congenital amaurosis, a rare genetic disease that primarily affects the retina, the tissue at the back of the eye that detects light and color. Serious visual impairment begins in childhood, and sight generally fades to near or total blindness.
Molly’s vision, never good, had deteriorated over the years. While she’d always attended regular classes, she also learned how to read Braille and use a cane. Trick-or-treating was a misery. She kept a full-spectrum light on her desk at school.
But in August 2013, Molly underwent twin eye surgeries. Doctors at the University of Iowa Hospitals and Clinics injected her with a virus loaded with the correct copies of her faulty gene, part of a clinical trial of a new gene therapy.
Today her vision, though not perfect, has improved to the point where she can see many of the things her family once had to describe to her. She can also think about learning to drive.
This month a U.S. Food and Drug Administration advisory panel voted unanimously to recommend approval of the treatment she received. If the therapy is approved — and the agency rarely reverses such expert recommendations — the treatment will become the first gene therapy in the United States for an inherited disease and the first in which a corrective gene is given directly to the patient. A decision is due by Jan. 12.
Meanwhile, Molly and her family are featured in a film called “The Gene Doctors” that’s streaming this month on PBS. The film, which also is airing on Nebraska Educational Television, focuses on the efforts of researchers across the country who are working to address conditions such as Leber’s, cystic fibrosis and muscular dystrophy and follows the journeys of families living with genetic illnesses.
And it has been a journey, said Laura Troxel, Molly’s mother, noting that the family has sprinkled in some humor along the way.
A nurse, Troxel said she first noticed that her infant daughter, the second of three, would do whatever she could to look toward a light, even when nursing.
The local experts they saw suspected Leber’s. The Troxels traveled to the University of Iowa, where the condition was diagnosed. Eventually researchers there identified the faulty gene, which turned out to be the same one targeted by the gene therapy.
Called Luxturna, it was developed by a Philadelphia-based biotech startup called Spark Therapeutics, based on research at Children’s Hospital of Philadelphia. Ryan Troxel, Molly’s father, said the researchers thought the therapy could help Molly. And there were hopeful signs in early tests in dogs as well as humans, including a New York boy who’d seen significant improvements in a 2008 test.
But Molly also had severe epilepsy, a condition that proved far scarier and held her back more than her limited vision. Not that much has actually held Molly back. Even before the procedures, her parents said, Molly liked to ride her bike fast. She enjoys skiing, a game called goal ball and other active pursuits.
“Molly’s a daredevil,” Laura Troxel said. “She has no fear.”
To be accepted as a candidate for the trial she had to go through genetic testing, which ultimately showed that the two conditions weren’t connected, and be seizure-free for a year. Once she was, she got back in the trial, with the Iowa doctors going to bat for her.
Laura and Ryan Troxel, understandably, had some concerns. The field of gene therapy had suffered a setback with the death of a young man in 1999. Ryan Troxel said the couple initially wanted to treat just one eye, thinking to preserve what little vision Molly had in case the treatment didn’t work. But the clinical trial protocol called for both.
And Molly wanted to go ahead. As early as age 7, she’d made a card for one of the Iowa researchers that read, “I just want to see. I don’t care what you have to do to me.”
Dr. Stephen Russell, a professor of ophthalmology at the University of Iowa’s Carver College of Medicine, treated Molly’s right eye first and the left a week later. Russell, the principal investigator for the Iowa portion of the trial, and his team treated 11 patients. The other 20 were treated at the Philadelphia hospital.
Nothing miraculous happened at first. But then Molly saw the moon. And the twinkle lights. And the canine eyelashes. She can see better now in low light, and go trick-or-treating with her sisters. Her visual acuity now runs 20/200 with glasses. Before the procedures, it was 20/400 with correction.
“Molly’s very capable of succeeding whether she has vision or not, but a little more vision doesn’t hurt,” Laura Troxel said.
Indeed, the family’s real hope is that the treatment will stop the disease’s progression.
Russell, who attended the FDA hearing, said the aim was to improve patients’ function. Treating both eyes improves peripheral vision, which is important in navigating the world.
Specifically, the trial addressed a patient’s ability to see in the dark, using an obstacle course to measure performance. Ninety-three percent of the patients, or all but two, improved by at least one light level. Seventy percent improved to the lowest light level. One of the two who didn’t improve as much, however, improved on another measure.
“You have to remember, these patients are going relentlessly blind,” he said. “Stopping it would have been good. Making it better is better ... Molly is a success story any way you look at it.”
Ideally, he said, researchers anticipate treating patients at a younger age, although that can pose surgical risks.
Though there have been questions about how long the treatment will last, it should prove durable, Russell said. The cells getting the new genes are no longer dividing, so there should be no dilution of the gene. Though the effect seemed to wear off in earlier trials, improvements were made before the last one.
“We have data out to four years, and we have not seen any drop-off,” he said. The researchers will follow patients for 15 years under FDA safety requirements.
On the larger stage, final approval of the therapy could help pave the way for future gene therapies. The virus delivery system the researchers used proved safe, giving them an excellent platform to work with, Russell said.
Another Iowa researcher, a geneticist, recently published a study indicating that the genes for a significant number of inherited eye diseases are small enough to fit inside the delivery system.
Researchers also have learned over the past 20 years that there are lots of ways to target genetic diseases other than replacing entire genes, said Dr. Omar Abdul-Rahman, a director of the genetic medicine department at the University of Nebraska Medical Center’s Munroe-Meyer Institute, who was not involved in the research. They’re exploring methods such as changing single mutations in genes and creating drugs that alter the way genes are transcribed into proteins.
The work on diseases caused by a single gene, like Leber’s, also is teaching researchers about more common conditions, such as heart disease, that have a genetic component.
“In the past, genetics has focused on diagnosis,” he said. “Now we have to think about treatments.”