Eyesight improves 100-fold after gene therapy trial

The vision of people with a rare inherited disease that causes vision loss in childhood improved 100-fold after receiving gene therapy to treat the genetic mutation that causes the disease. Some patients even saw their vision improve 10,000-fold after receiving the highest dose of the therapy, according to researchers at the Perelman School of Medicine at the University of Pennsylvania who co-led the clinical trial published in The Lancet.

“This 10,000-fold improvement is equivalent to a patient’s ability to see their surroundings on a full moon night outdoors, instead of needing bright indoor lighting before treatment,” said study lead author Artur Cideciyan, Ph.D., research professor of ophthalmology and co-director of the Center for Inherited Retinal Degeneration.

“One patient reported being able to move around outdoors at midnight for the first time only by the light of a campfire.”

A total of 15 people participated in the phase I/II trial, including three pediatric patients. Each patient had Leber congenital amaurosis resulting from mutations in the GUCY2D gene, which is essential for producing proteins that are essential for vision. This specific disease, which affects fewer than 100,000 people worldwide and is abbreviated LCA1, causes significant vision loss starting in early childhood.

All subjects had severe vision loss, with their best vision measurement being 20/80 or worse, meaning that while a person with normal vision could see an object clearly at 80 feet, these patients would have to move at least 20 feet to see it.

Glasses offer limited benefit to these patients because they correct abnormalities in the eye’s optical focusing ability and are unable to treat medical causes of vision loss, such as genetic retinal diseases like ACL1.

The trial tested different dosage levels of the gene therapy, ATSN-101, which was adapted from the microorganism AAV5 and was surgically injected under the retina.

For the first part of the study, cohorts of three adults each received one of three different dosages: low, medium, and high. Assessments were conducted between each dosage level to ensure they were safe before increasing the dosage for the next cohort.

A second phase of the study consisted only of administering the high doses to a three-person adult cohort and a three-person pediatric cohort, again after safety reviews of the previous cohorts.

Improvements were seen quickly, often within the first month of treatment, and lasted for at least 12 months. Observations of participating patients are also ongoing. Three of six high-dose patients who were tested to follow a mobility path in different light levels achieved the maximum possible score. Other tests used visual acuity charts or measured the faintest flashes of light patients perceived in a dark environment.

Among the nine patients who received the maximum dose, two saw their vision improve 10,000-fold.

“Although we had already predicted significant vision improvement potential in LCA1, we did not know how responsive patients’ photoreceptors would be to treatment after decades of blindness,” Cideciyan said. “It is very gratifying to see a successful multicenter trial that shows gene therapy can be extremely effective.”

The study was primarily aimed at determining the safety of gene therapy and its different dosage levels. The researchers found that some patients experienced side effects, but the vast majority of them were related to the surgery itself.

The most common side effect was conjunctival hemorrhage, the rupture of small blood vessels under the clear surface of the eye, which healed. Two patients had eye inflammation that was reversed with a course of steroids. No serious side effects were linked to the study drug.

This work follows another successful eye trial at Penn that restored vision in patients with another form of LCA. Earlier in 2024, CRISPR-Cas9 gene editing was used to improve vision in many patients with a form of LCA linked to mutations in the CEP290 gene.

Co-led by one of the new paper’s co-authors, Dr. Tomas S. Aleman, the Irene Heinz-Given and John LaPorte Research Professor of Ophthalmology and co-director with Cideciyan of the Center for Inherited Retinal Degenerations, the study used similar tests and was the first time children had been involved in gene-editing work.

“The success of the treatment in our most recent clinical trials, combined with our previous experience, gives us hope for a viable treatment for approximately 20 percent of childhood blindness caused by inherited retinal degenerations,” Aleman said.

“The focus now is on refining treatments and treating the early manifestations of these conditions once their safety has been confirmed. We hope that similar approaches will lead to similarly positive results in other forms of congenital retinal blindness.”

Approval of this experimental drug for clinical use now requires another trial, in which participants are randomized to receive a dose of treatment and where patients and people studying the trial do not know who is receiving what. This would help avoid any potential bias in the results.