Gene Therapy Shown to Improve Vision in Congenital Blindness

An investigational gene therapy has shown promise for improving functional vision and restoring light detection in long-dormant rods and cones in the retina in adults and children with a rare form of congenital blindness.

The early-phase clinical trial, published in The Lancet, evaluated the gene therapy, ATSN-101, in 15 patients with Leber congenital amaurosis (LCA) 1, which is a type of LCA caused by biallelic mutations in the GUCY2D gene. Twelve-month results showed the highest dose treatment was linked to an improved ability to see fine details, measured as a −0.16 change in logMAR, or about eight letters on an eye test. That effect translates into almost two lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, according to senior study author Artur Cideciyan, PhD.

“Visual acuity improvements were small,” said Cideciyan, codirector of the Center for Hereditary Retinal Degenerations at the Scheie Eye Institute at the University of Pennsylvania in Philadelphia. “There was a trend for a slight improvement, but not a statistically significant one.”

A two-line change on the ETDRS chart could be the difference between 20/200 vision, the threshold for legal blindness, and 20/125 vision. A visual acuity measurement of 20/200 means a person who is 20 feet from the eye chart can see what a person with 20/20 vision can see from 200 feet away.

But the more exciting results, Cideciyan said, involve gains in the ability of patients to detect light.

“An important concept that comes out of this study is that you can have a photoreceptor that is waiting dysfunctionally for decades and then all of a sudden, within a matter of 8-10 days, they start functioning when they receive the gene,” Cideciyan said. “That is very hopeful about any of these long-term congenital diseases; the body hasn’t shut off the molecular machinery in dysfunctional photoreceptors, such that they can never be treated. So in that sense, it’s very promising.”

Putting Light on Photoreceptors

“This is the first time you show a really dramatic change in vision function, and it gives us hope for all the other inherited retinal diseases out there,” Darius Moshfeghi, MD, chief of the Retina Division at Byers Eye Institute at Stanford University in Stanford, California, and a pediatric retina specialist, told Medscape Medical News. “Maybe some of our baseline assumptions about how durable photoreceptors are need to be reevaluated.”

This study is the first to use gene therapy in inherited retinal disease that showed such a dramatic restoration of function, Moshfeghi added.

ATSN-101 is a recombinant AAV5 gene vector that contains human GUCY2D complementary DNA, a key enzyme in photoreceptors. A retina surgeon injects the vector under the retina in the operating room.

The trial used escalating dosing in three cohorts of adults (N = 9): A low dose, 1 × 10¹⁰ vector genomes per eye (vg/eye); a middle dose, 3 × 10¹⁰ vg/eye; and a high dose, 1 × 10¹¹ vg/eye. After the high dose showed preliminary evidence of vision improvement, an additional six patients — three adults and three children — were given the high dose.

In the high-dose patients, the average change in scores on the dark-adapted full-field stimulus test (FST), which measures the dimmest light a person can perceive in the dark, was 20.3 decibels (dB) in treated eyes vs 1.1 dB in untreated eyes, demonstrating an improved ability for photoreceptors to capture light. Six of the nine high-dose patients had at least a 10-dB improvement in FST, ranging up to 46.5 dB, a more than 10,000-fold gain.

“Visual acuity was not the main efficacy outcome,” Cideciyan said. “The main efficacy outcome was change in ability for the photoreceptors to catch light, which is the primary purpose of photoreceptors. Once they are able to catch light, a higher level of vision can occur, such as spatial acuity, color vision, motion detection, and reading. All of those are predicated on first the photoreceptors being able to catch light.”

The findings are significant because they demonstrate that photoreceptors that have been dysfunctional for decades can be made functional again, Moshfeghi said. “It gives us hope that in other applications, we have the potential for a return of function as long as the photoreceptors are there,” he said.

Safety Outcomes Hint at Learning Curve

As for safety outcomes, the primary endpoint of the early phase study, the investigators reported 68 treatment-emergent adverse events (TEAEs) related to the operation, but no serious complications related to the drug.

Eight patients had hypotony of the eye, which is when intraocular pressure drops < 6.5 mm Hg (normal is between 10 and 20 mm Hg). One patient with light perception in the treated eye had a macular hole that formed during surgery that resulted in no improvement in vision. Another experienced inflammation of the inner globe of the eye that caused a retinal detachment, which was treated with surgery. The same patient later developed a cataract, Cideciyan said.

Moshfeghi said the level of TEAEs seemed high. He noted that surgery-related endophthalmitis, which can result in the loss of the eye, occurs in roughly 1 in 1000 people, and retinal detachment in about 1 in 100. “All of it signals to me that the technique has a learning curve to it,” he said.

Atsena Therapeutics funded the study. Cideciyan disclosed financial relationships with Atsena and Sanofi. Study coauthors Andreas Lauer, MD, and Mark Pennesi, MD, PhD, also disclosed relationships with Atsena. Moshfeghi has no relevant disclosures.

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.