Spark Therapeutic’s experimental treatment for a hereditary form of blindness called Leber congenital amaurosis (LCA) is close to being available to patients. An advisory committee to the FDA unanimously endorsed the treatment in October. Then, at the American Academy of Ophthalmology meeting earlier this month, researchers reported positive results from their phase 2/3 trial, showing that patients were able to see well enough to navigate a maze after receiving the gene therapy. If the FDA approves the therapy, known as Luxturna (voretigene neparvovec), in January, it will become the first treatment in the U.S. to reverse an inherited disease.
In LCA, inherited blindness begins in childhood and progresses slowly. The extent of vision loss varies from patient to patient, but in severe cases those with LCA can become completely blind by age 40. It is estimated that between 1,000 and 3,000 people are affected by the disease in the U.S. Their LCA can be caused by mutations in any of 22 different genes, although Luxturna only targets one of them — a gene called RPE65, which is expressed in retinal pigment cells.
Without the correct RPE65 gene, visual pigments don’t form properly, and retinal cells can’t respond to light. To restore eyesight, Luxturna supplies a healthy, non-mutated copy of RPE65 via a harmless adenovirus (AAV) that is injected directly into a patient’s retina.
In trials, 27 out of 29 — or 93 percent — of patients gained significant improvement in vision that lasted up to three years. Patients showed increases in light sensitivity, peripheral vision, and the ability to navigate a maze. While the therapy wasn’t able to restore normal vision, it provided enough improvement to patients that they could see light and shapes.
“These are truly spectacular results,” says Yasha Modi, assistant professor of ophthalmology at NYU Langone Health. “This is a huge step forward for gene therapy because it demonstrates efficacy.”
And while there are relatively few patients who will benefit from this specific treatment for LCA, this is only the beginning. “It’s a stepping stone,” says Jean Bennett, scientific director of the study and a professor at University of Pennsylvania’s Perelman School of Medicine. “More than 260 blinding conditions are caused by a mutation in a single gene. Theoretically, this same approach could be used for each of these other mutations, and clinical trials are moving forward on many of those others right now.”
Beyond single-gene mutations, researchers are looking at ways to use the same AAV vector to treat other eye diseases, like delivering an agent to block abnormal blood vessel growth in wet form macular degeneration. This would mean that people with the age-related eye disease would need fewer trips to the doctor for monthly injections, which are the current form of treatment. And blocking abnormal blood vessel growth could be applied to other diseases, such as retinopathy of prematurity and diabetic retinopathy.
“The eye is a really good organ to take these first steps with because of its features,” says Bennett. “It has a benign immune response to foreign agents. You only need a small amount to treat the tissue. But this approach of augmenting genes can be used in other organ systems or more systemically.”
Compared to Kymriah, which was the first FDA-approved gene therapy for acute lymphocytic leukemia, the mechanism by which gene therapy for LCA works is very different. To make Kymriah, T cells are harvested from the patient, put in a petri dish, infected with the recombinant virus, allowed to multiply, then injected back into the patient. And the virus isn’t replacing a mutated gene, but adding a receptor to T cells which binds to the leukemic cells and destroys them. Luxturna, in contrast, delivers a corrected gene directly into the targeted tissue.
While patients are undeniably excited about the potential treatment, Modi says he is careful to temper enthusiasm. “Ninety percent of LCA patients won’t qualify for this therapy,” he says. “I tell patients that while there isn’t a currently available treatment for what you have, genetic testing will allow us to build a database and offer patients early enrollment in clinical trials based on their specific genetics.” But this study provides proof of principle that gene therapy can be used to deliver a correct copy of a gene to cells and make them function properly once more, he says. Now the trick is expanding the number of genes, and thus patients, that can be treated.