A New Treatment for Blindness Comes From Gene Therapy

Three months after Misty Lovelace was born, she was already going blind. In first grade she could still read small print, but within a few years her schoolbooks were binders of large-print pages. To navigate hallways, she memorized the route or depended on a teacher or friend. Her sight was “like having really dark sunglasses and looking through a tunnel,” she recalls. In fifth grade, someone brought in a mobile planetarium to show the students lights representing the stars. Misty pretended she could see them.

When she was 12, doctors determined that Misty’s blindness had a genetic cause called Leber congenital amaurosis (LCA). Fortunately, a husband-and-wife team at the University of Pennsylvania—Jean Bennett and Albert Maguire—were testing a potential cure, and Misty traveled from Kentucky to take part in the study. A day after the surgery, doctors took off her eye patch. “I saw a burst of color. Everything was so much brighter,” she recalls. For the first time in years, she could clearly see her mother’s face, her grandmother’s wrinkles, the fabric seams in her stuffed animals. At home in the backyard pool one night, she looked up and started screaming. “I see these little lights and they’re all blinking. I started to freak,” she recalls. Her mother rushed out, thinking chlorine was hurting her daughter’s treated eye. Misty could finally see the stars.

Misty’s treatment became available to the public during the past year under the name Luxturna. Its FDA approval in December 2017 was huge news—not only for the 1,000 to 2,000 Americans with Misty’s type of LCA, but for people with other genetic diseases that could one day be cured through gene therapy.

I’d last visited Bennett and Maguire ten years ago when they were treating their first patients. This past July, they reflected on their journey while brunching on their patio in the Philadelphia suburb of Bryn Mawr. Mercury, a brown-and-black Briard dog, panted in the heat. Born blind, he was one of the couple’s earliest research subjects. His mother, Venus, another formerly blind dog, was staying cool indoors.

“There were innumerable obstacles along the way,” said Bennett, 63, curled up in a chair with her coffee. Maguire, 58, handed me a jar of honey from his beehives. He told me his wife deserved credit for frequently staying up working late while he was “snoring in bed.”

The two met and married at Harvard Medical School—Maguire was becoming an eye surgeon, and Bennett, who also had a PhD in developmental biology, was about to enter the new field of gene therapy. Working together, the pair showed they could improve the vision of mice born with genetic blindness. In 2000, they tested this on Briard dogs who had been born with defective copies of RPE65, the gene affected by LCA.

RPE65 is crucial for the visual cycle in mammals. When light hits sensitive pigments in the retina, it launches a series of reactions that make sight possible. Everyone has brief moments when this process falters—for instance, after the eye is overwhelmed by a camera flash. In healthy eyes, these moments are fleeting. But people who have two defective copies of RPE65 don’t react to light properly. Over time, the light-sensing cells—the rods and cones—die off, causing their vision to disappear.

Working with the dogs, the scientists modified an adeno-associated virus (a small virus that’s harmless to mammals) so it carried DNA with normal RPE65. Then they injected the virus into one eye of each blind puppy. Within days, the frightened dogs who bumped into objects had turned into active, sighted animals.

By 2007, it was time to try the procedure on people. The medical community was still reeling from the 1999 death of teenager Jesse Gelsinger in an unrelated gene therapy study at Penn. Starting this new research was risky. But Gelsinger had been treated for a metabolic liver disease, and the eye had certain advantages: It was easy to access, and only a small area of tissue, not the entire organ, needed to receive the gene. Plus, doctors could try the therapy in one eye before moving on to the second. (They didn’t expect an issue with patients making antibodies to the virus, since eyes are largely shielded from the body’s immune response.)

Maguire and Bennett, together with the Children’s Hospital of Philadelphia (CHOP), began testing a low dose of this treatment in three young adults with RPE65 mutations. Maguire injected a pea-size drop under their retinas containing billions of RPE65-carrying viruses. The patients’ vision improved—they could read signs and see patterns in rugs, and they could read more lines on an eye chart. One Saturday at home, Bennett was looking at data on a patient’s pupil contraction and raced upstairs to awaken Maguire from a nap. “We were thrilled!” she says.

From there, the team showed they could successfully treat the patients’ second eyes. The next step was to seek FDA approval. In 2013, the team founded Spark Therapeutics, a biotech firm, to develop and fund a larger trial at CHOP and at the University of Iowa and carry out other work to get the first U.S. approval for a virus-delivered treatment for a genetic disease. “There was no road map, and this was a very heavy lift,” says Katherine High, a hematologist and gene therapy researcher who helped lead the trials at CHOP and went on to become president of Spark.

Several children have now received Luxturna as part of their clinical care. The treatment is $850,000 for both eyes. “The cost horrifies me personally,” admits Bennett. (Neither she nor Maguire profits financially from the therapy.) High says the price is steep because “the current system is not designed for one-time high-value treatments.” She notes that drugs for a condition like hemophilia cost as much as $400,000 a year over an entire lifetime. “One would hope the system would reward therapies that achieve their effects through a single treatment, but that is not yet the case,” High says.

It’s unknown how long Luxturna’s benefits will last, but Maguire says patients treated up to 11 years ago still have stable vision in the second eye, which received a higher dose than the first. Many of them can now walk without a cane and tell colors apart. Those on the younger end of the 4- to 44-year-old age range report the most benefits, since they’d lost fewer photoreceptor cells: Kids who couldn’t play outdoors after dark, or ride a bike without help, are now able to do those things. Some of the teenagers are eligible for driver’s licenses. They are able to play varsity soccer and join the cheerleading squad. Their social lives blossomed once they could read friends’ faces.

The couple accomplished all this while raising three children, now grown. Their house is still decorated with the kids’ art, along with Ma-guire’s paintings of cows. Their oldest child, Sarah Maguire, is 32 and a postdoctoral researcher at Johns Hopkins, where she’s tweaking the genes of mosquitoes to make them dislike the smell of humans. She recalls a fairly normal childhood, despite having “really quirky” parents. “My dad would come home and start dancing with the dogs like Pee-wee Herman,” she says. When she brought insect research home on a visit last year, Bennett eagerly equipped a bathroom with a humidifier and heater to keep the bugs alive.

One of these days, Bennett and Maguire hope to retire and raise cows, sheep or crops—“Berkshire bud,” Maguire jokes. For now, they’re hard at work at the Center for Advanced Retinal and Ocular Therapeutics, or CAROT, which Bennett founded at Penn in 2014. When I visited, researchers were making gene-carrying viruses for new trials. The excitement was palpable: Luxturna has paved the way for the FDA to approve a multitude of promising treatments, not just for the eye but for other organs and diseases being studied elsewhere. “There was no path before,” says Bennett, “and now there is.”

Misty Lovelace is now 19, and her vision is about 20/64 with glasses. When the sun is shining, she says, “I can do anything.” She hopes to soon start her own business training horses. “I can’t believe it was me,” she says, looking back on her role in Bennett and Maguire’s study. “It’s just, wow, like hitting the lottery. They did it. They opened the doors for everybody.”

Jocelyn Kaiser | READ MORE

Jocelyn Kaiser is a staff writer for Science magazine.