Gene Therapy for Eye Disease Shows Benefits and Limitations

LCA is an inherited disorder that causes vision loss in childhood. It primarily affects the retina, the light-sensitive tissue at the back of the eye, as seen in this retinal photo.National Eye Institute

When you watch a sunset, an intricate series of events takes place in your eyes. Light passes through the front part of the eye and is refracted and focused on the retina, a thin, delicate tissue at the back of the eyes. The retina contains photoreceptor cells that detect light and convert it into electrical signals that are sent to the brain.

The photoreceptor cells rely on a protein called RPE65 to recharge their light sensitivity and for long-term survival. About 10% of people with Leber congenital amaurosis (LCA), an inherited disorder that causes vision loss starting in childhood, have an altered form of the gene RPE65. Since LCA is caused by a faulty gene, scientists reasoned that they might be able to treat people by inserting a healthy gene. This strategy, in which genes are used to treat or prevent a disease, is known as gene therapy.

Clinical trials of experimental gene therapy for LCA and other diseases that affect the retina have been progressing for several years. One study supported by NIH’s National Eye Institute is being conducted by a team that includes Drs. Samuel G. Jacobson and Artur V. Cideciyan from the University of Pennsylvania, and Dr. William W. Hauswirth from the University of Florida, Gainesville.

The group treated 15 people who have LCA with retinal injections of a harmless virus engineered to carry normal RPE65 genes. As reported previously, participants who received the gene therapy injections were able to see dim lights that they weren’t able to see before treatment. This finding indicated that the newly introduced RPE65 gene was functional and was increasing the light sensitivity of the retina. The researchers determined that 4 of the 15 participants started relying on an area of the retina near the gene therapy injection site for seeing letters.

The participants routinely underwent extensive tests of their vision and imaging of the retina for up to 6 years after treatment. Follow-up results, reported in early 2013, found that while gene therapy improved vision for at least 3 years, photoreceptor cells continued to degenerate. Additional imaging results for 3 of the treated participants were published on May 14, 2015, in New England Journal of Medicine. Using sophisticated imaging capture and analysis techniques, the scientists were able to map the area of retinal improvement and track changes with time.

The team found that gene therapy improved patients’ eyesight and the sensitivity of the retina within a month of treatment. This was followed by a slow expansion of the area of improvement for up to 3 years after treatment. The area of improvement, however, then underwent a contraction.

The researchers determined that the RPE65 gene therapy boosted the photoreceptor cell recharge cycle, but didn’t delay cell death. The cells continued to die at the same rate as they do in the natural course of the disease, regardless of treatment.

Another study in the same journal—by researchers at Moorfields Eye Hospital and University College London—found that retinal sensitivity improved in 12 LCA patients treated with gene therapy, but then diminished after 12 months.

“Gene therapy for LCA demonstrated we could improve vision in previously untreatable and incurable retinal conditions,” Jacobson says. “Even though the current version of the therapy doesn’t appear to be the permanent treatment we were hoping for, the gain in knowledge about the time course of efficacy is an opportunity to improve the therapy so that the restored vision can be sustained for longer durations in patients.”