One of the greatest gene therapy success stories to date (which occurred in 2017) was the FDA approval of Luxturna—an AAV-based gene therapy to treat inherited retinal disease. The gene therapy treats patients with Leber congenital amaurosis caused by mutations in RPE65.
Now, new results show promise in the treatment of another inherited eye disorder, Leber congenital amaurosis 1 (LCA1), caused by mutations in GUCY2D. LCA1 is a rare inherited retinal disease that typically causes blindness in early childhood. The aim of the study was to evaluate the safety and preliminary efficacy of ascending doses of ATSN-101—a subretinal AAV5 gene therapy for LCA1. The findings suggest that the vision of some patients was 100 times better after the gene therapy, with some patients experiencing a 10,000-fold improvement in their vision after receiving the highest dose of the therapy.
This work is published in The Lancet, in the paper, “Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study.”
A total of 15 people participated in the Phase I/II trial, including three pediatric patients. All subjects had severe vision loss with their best measure of vision being equal or worse than 20/80—meaning if a typically-sighted person could see an object clearly at 80 feet, these patients would have to move up to at least 20 feet to see it.
The trial tested different dosage levels of the gene therapy, ATSN-101, which was surgically injected under the retina. For the first part of the study, cohorts of three adults each received one of the three different dosages: Low, mid, and high. A second phase of the study involved only administering the high dosage levels to both an adult cohort of three and a pediatric cohort of three.
Improvements were noticed quickly, often within the first month after dosage, and lasted for at least 12 months. Observations of participating patients are ongoing. Three of six high-dosage patients who were tested to navigate a mobility course in varying levels of light achieved the maximum possible score. Other tests used eye charts or measured the dimmest flashes of light patients perceived in a dark environment.
Of the nine patients who received the maximum dosage, two had a 10,000-fold improvement in vision.
“That 10,000-fold improvement is the same as a patient being able to see their surroundings on a moonlit night outdoors as opposed to requiring bright indoor lighting before treatment,” said Artur Cideciyan, PhD, a research professor of ophthalmology and co-director of the Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania (UPenn). “One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.”
“Even though we previously predicted a large vision improvement potential in LCA1, we did not know how receptive patients’ photoreceptors would be to treatment after decades of blindness,” said Cideciyan. “It is very satisfying to see a successful multi-center trial that shows gene therapy can be dramatically efficacious.”
The majority of reported side effects were related to the surgical procedure itself. The most common side effect was conjunctival hemorrhage, the breakage of small blood vessels underneath the clear surface of the eye, which healed. Two patients had eye inflammation that was reversed with a course of steroids.
This work comes on the heels of another successful ophthalmological trial at UPenn restoring sight in patients with a different form of LCA. Earlier in 2024, CRISPR-Cas9 gene editing was used to improve the sight of many patients with a form of LCA tied to mutations in the CEP290 gene. The study was the first time children were involved in any gene editing work.
“The treatment success in our most recent clinical trials together with our earlier experience brings hope for a viable treatment for about 20% of infantile blindness caused by inherited retinal degenerations,” said Tomas Aleman, MD, research professor in ophthalmology and co-director with Cideciyan of the Center for Hereditary Retinal Degenerations. “The focus now is on perfecting the treatments and treating earlier manifestations of these conditions once safety is confirmed. We hope similar approaches will lead to equally positive outcomes in other forms of congenital retinal blindness.”
