One of the most heralded successes of gene therapy may not be the permanent fix that many had hoped. Leaders of two clinical trials report this week that a treatment that restored some vision to blind patients begins to fade within a few years. A third group, however, says their patients, who received a different version of the therapy, are retaining their improved vision, and a company is moving ahead with efforts to gain regulatory approval for their treatment.
It is not a huge surprise that the treatment effects may not last, says eye disease researcher Mark Pennesi of Oregon Health & Science University in Portland, who is running a similar trial. “These are complex diseases and everything that’s been done is sort of first generation,” he says. “The fact that there was biological activity at all is a milestone.”
At issue is gene therapy for a rare form of inherited blindness known as Leber’s congenital amaurosis (LCA) that results in complete vision loss by about age 40. About 10% of cases are due to a mutation in retinal pigment epithelium 65 (RPE65), a gene that codes for an enzyme that helps retinal cells make rhodopsin. The pigment is needed by photoreceptor cells—the retina’s light-sending rods and cones—and when RPE65 is mutated, the photoreceptor cells gradually die.
In 2007, in the first-ever effort to use gene therapy to treat people with blindness, three separate teams in the United States and the United Kingdom launched clinical trials for the RPE65 type of LCA. A surgeon injected one eye of each patient with a solution containing a harmless virus that ferried a good copy of RPE65 into retinal cells.
As soon as a few days after the treatment, many patients’ retinas were more sensitive to light, and they were better at navigating a maze, particularly in low light. Perhaps most compelling were accounts from overjoyed patients who shared their stories publicly. A Canadian man named Dale Turner said colors were more vivid after the treatment. And a boy named Corey Haas from upstate New York said he could now ride a bike alone, play baseball, and read large-print books. His story inspired a book, The Forever Fix, which heralded the LCA trials as part of the wave of successes for gene therapy, which was recovering from several setbacks—including the death of a patient and cancer in others—in the late 1990s and early 2000s.
Two years ago, however, a team led by Samuel Jacobson at the University of Pennsylvania (UPenn), which runs one of the U.S. trials for LCA, sounded a note of caution: They reported that although their 15 patients who had regained some vision could still see better, their photoreceptor cells were continuing to deteriorate.
And now it seems that has translated into waning vision. Online yesterday in The New England Journal of Medicine (NEJM), Jacobson’s group reported that in three patients with long-term results, the area of the retina with increased visual sensitivity peaked within 1 to 3 years and then began to shrink, although it remained larger than before treatment. The U.K. team reports in a separate paper online today in NEJM that although six of 12 patients had improved night vision, in their trial, too, the benefits faded within 3 years.
The research leader of the U.K. trial, Robin Ali of University College London, points out that the original vision improvement in their patients fell far short of what they saw in dogs receiving the same therapy. He thinks that’s because the patients’ retinas didn’t get as much RPE65 as they needed. “To make a truly effective therapy, it’s very important to restore normal function,” Ali says. His group is now planning a new trial with a “much more powerful vector” or viral system for delivering the gene, which should result in higher RPE65 expression, he says. But UPenn’s Jacobson and co-worker Artur Cideciyan caution that higher doses come with a trade-off—higher toxicity. Their group thinks they may need to treat more of the retina and perhaps give patients another drug that slows photoreceptor degeneration.
What’s not clear is whether the waning results seen in these two trials will be seen in the third study. UPenn gene therapy researcher Jean Bennett, who heads that study (which is separate from Jacobson’s) and reported the most dramatic improvements in patients’ vision, says those gains seem stable for as long as 7.5 years. “It would be naive to say it may not decrease over time, and we’re still analyzing the results,” she says. But so far, “in the majority of patients, we see persistence of an improvement in light sensitivity,” she says. She’s reluctant to draw conclusions from just three of Jacobson’s 15 patients; she thinks the weaker vector used by the U.K. group may explain why their patients are losing their improved vision.
Spark Therapeutics in Philadelphia, Pennsylvania, which is testing the Bennett group’s therapy in a phase III clinical trial needed to seek regulatory approval, also maintains that the NEJM results may not be relevant to their product. Spark CEO Jeff Marrazzo says their more potent vector and differences in how the treatment is made, such as the company’s use of a surfactant to make sure the vector doesn’t stick to the vial when the surgeon injects it, may result in a higher dose of the RPE65 gene getting into retinal cells and long-lasting effects.
Asked if the decline may simply take longer, “I guess it’s possible,” Marrazzo says. But like Bennett, he says that’s no reason not to proceed with regulatory approval. He points to patient testimonials of how much their lives have improved from being able to see colors and make out their children’s faces and navigate more easily. “At the end of the day, that’s what matters to us is, what it means from a functional perceptive for patients.”