Indeed not. Christian was twelve years old when his parents heard about an experimental gene therapy being developed by Jean Bennett, a colleague of Wilson’s at the University of Pennsylvania, and enrolled him. The results were almost literally off the charts. David Dobbs described the transformation: “Guardino could see. Everything that had posed an obstacle before—light and dark, steel and glass, the mobile and the immovable—now brought him pleasure. The world had opened before him.”2 That pleasure was shared with millions of TV viewers when Guardino won something called the “Golden Buzzer.” Bennett proudly shows the clip in her talks as Guardino disappears from view under a shower of confetti.
Bennett has dedicated her career to finding a therapy for LCA. In the early ’80s, she’d spent time in the lab of French Anderson, who advised her to “go to Harvard Medical School, learn about the diseases you want to treat, go back to the lab and start working on them.”3 She followed his advice: at Harvard she met her future husband, Al Maguire, a retinal surgeon. In 1990, inspired by Anderson’s historic gene therapy trial, Bennett and Maguire discussed the prospects of transferring genes to the retina. There was just one small problem: there were no known genes, no animal models, no natural history, no vectors, no surgical methods, and no outcome measures.
Bennett’s naïveté proved to be a blessing. After moving to Penn in the early 1990s, she realized that “the retina is pretty cool and that it would actually be fun to look at retinal gene therapy.”4 Wilson and his colleagues were building new facilities and developing novel vectors. Eyes are “post-mitotic,” meaning cells don’t divide, which would stop the delivered transgene from becoming diluted. And there was little risk of triggering an immune response. (The eye is an “immune privileged organ,” a mini isolation chamber with a blood barrier and no lymph system.5) The effects of the therapy could be tested in various ways and could be measured against the ideal control—the patient’s untreated eye.
The pieces finally came together in 1997, when researchers identified the gene mutated in one of many forms of LCA. The defective gene, RPE65, was one of hundreds of mutated genes that constitute hereditary blindness. There are some 7 million blind people in the United States, including 700,000 children. With only about 1,000 LCA patients in the United States, tackling this disorder was a drop in the bucket. But Bennett had to start somewhere. She learned that the Penn veterinary college housed a breed of dogs with the same gene mutation. A blind four-year-old briard sheepdog mix named Lancelot joined the quest to cure LCA. (Lancelot’s role was essential as the viral vector didn’t work in mice.)
In dogs as in humans, the pace of the retinal degeneration is slow, giving the researchers time to assess the benefits of their treatment. Maguire injected the therapeutic RPE65 gene, packaged in AAV, under the retina of Lancelot and two other dogs. Within a few weeks, Lancelot’s demeanor changed: he began to see, watching and following the veterinary staff.6 He became something of a canine celebrity, even visiting the United States Congress. He produced a large family with his sibling, Guinevere, and was eventually adopted by Bennett.
That early momentum stalled as the entire gene therapy community reeled from the Gelsinger tragedy. But in July 2005, Katherine High, a colleague at Children’s Hospital of Philadelphia (CHOP), walked into Bennett’s office and made her an offer she couldn’t refuse: “How would you like to run a clinical trial at CHOP?” Five months later, Bennett and High addressed the Recombinant Advisory Committee (RAC) of the NIH. They were proposing to treat children—a controversial precedent for the gene therapy community. A pivotal moment came when patient advocates Betsy and David Brint recounted their daily struggle to help their youngest son, Alan, who has LCA, who needs the help of a dozen people to get through a day at school. Gene therapy, not to be overly dramatic, was Alan’s only hope. The RAC voted unanimously to grant approval.
The first of a dozen patients in the phase I LCA2 trial were treated in Naples in October 2007, led by Francesca Simonelli. During the procedure, the retinal surgeon inserted a canula the width of an eyelash, through which the genetically modified virus was delivered. The procedure results in a localized retinal detachment, which typically flattens within a few hours.
Maguire warned his wife not to read too much into the early vision results. But one test gave her hope: she performed a pupillometry—a light-mediated reflex—on a patient one month after the injection. Bennett recalled: “When the retina is functioning, it sends a signal through the optic nerve to the brain, which then sends a signal back to the muscle that controls the iris and causes it to constrict. Nobody can constrict a pupil at will, so I couldn’t contain myself when I saw this crystal-clear result.”7 She also called the test the bane of her existence, requiring hours measuring pupil diameters and analyzing spreadsheets strewn across her dining room table. But the results on the first three patients were unequivocal, and validated in the New England Journal of Medicine.8
Bennett’s youngest patient was Corey Haas. He entered the hospital in 2008 walking with a cane, holding his parents’ hands. After treatment, in a video that has done the rounds at medical conferences, Haas is asked to navigate a makeshift obstacle course comprised of junk retrieved from Bennett’s basement. With his treated eye patched, Corey couldn’t stop bumping into obstacles. But when the patch was switched, he navigated the maze without difficulty. Soon he was riding a bike, playing video games, and throwing a baseball, just like any healthy nine-year-old boy. Bennett’s other patients could suddenly see the moon, the stars, and their own faces. (“Mamma mia!” cried an Italian patient staying with Bennett on seeing her reflection for the first time.) Parents started clamoring for their child to have their other eye injected.
With no more dogs readily available, Bennett donated $10,000 to the lab of veterinary ophthalmologist Kristina Narfstrom to breed some new lines. Bennett picked up the puppies in person and adopted Venus and Mercury. Experiments showed little risk of immune response, allowing Bennett and Maguire to inject both eyes in patients in the Phase III trial. After twelve months, the control group was allowed to cross over to receive the drug as well. By all measures, the response a year later was as good as with the initial cohort of patients.9
In 2013, High cofounded Spark Therapeutics, and licensed Bennett and Maguire’s original patent. Four years later, an FDA advisory committee unanimously recommended the approval of therapy, Luxturna. Final FDA approval for the first in vivo gene therapy drugI came four months after approval of Kymriah, Novartis’s CAR-T cell therapy for acute lymphoblastic leukemia. In March 2018, hospitals in Boston, Miami, and Los Angeles administered Luxturna as a prescription drug for the first time. With a hefty list price of $425,000 per eye, it was no surprise that Spark should attract a big pharma suitor. Roche acquired Spark for $4.3 billion.
Delivering a keynote lecture at a conference in 2018, Bennett ended her talk on a curious note: she had just received a phone call from French Anderson, the father of gene therapy. Anderson had just been released on parole after serving twelve years of a fourteen-year prison sentence, having been convicted of sexual molestation of the teenage daughter of his senior lab director.10 Bennett insisted there was “abundant evidence of his innocence” and said he hoped to return to the field he’d helped launch almost three decades earlier. “I hope you’ll welcome him back,” she said.