Rare Diseases, Gene Therapy Improves Sight Up to 10,000 Times, Study

A patient with a rare form of hereditary blindness has seen her first star, experts say. Another has seen snowflakes for the first time. Others have been able to orient themselves outside the house or read the labels on their children’s Halloween candy. Something unthinkable when you grow up in the dark. Yet these are the concrete results reported by the scientific results obtained in a small study with a gene therapy developed by scientists at the University of Florida and aimed at the mutation that causes Leber congenital amaurosis type I or Lca1, a disease that leads to the loss of much of the vision already in early childhood. The improvement obtained following the administration was 100-fold, but some patients even experienced a 10,000-fold improvement after receiving the highest dose of the therapy, according to researchers at the Perelman School of Medicine at the University of Pennsylvania who co-directed the clinical trial.

The data are published in ‘The Lancet’. The 10,000-fold improvement described, explains the study’s lead author, Artur Cideciyan, co-director of the Center for Hereditary Retinal Degenerations, is that of “a patient who can see the surrounding environment on a full moon night outdoors, instead of needing strong indoor lighting” as before treatment. For example, one treated person “reported that for the first time he was able to orient himself outdoors at midnight only with the light of a campfire”. A total of 15 people participated in the phase 1/2 trial, including 3 pediatric patients, all ‘enrolled’ because of the diagnosis of Lca1 as a result of mutations in the gene Gucy2d (presence of 2 defective copies), essential for the production of proteins crucial for vision. This specific condition affects less than 100,000 people worldwide, about 3,000 in Europe and the United States.

The patients treated had severe vision loss, and the trial tested different dose levels of the gene therapy, Atsn-101, which was surgically injected under the retina. For the first part of the study, each cohort of three adults received one of three different doses: low, medium and high. Assessments were done between each dose level to ensure they were safe before increasing for the next cohort. A second phase of the study involved only giving the high dose levels to both adults and a cohort of three pediatric patients, again after safety reviews. Improvements were seen quickly, experts report, “often within the first month” of treatment, and lasted “for at least 12 months.” Patients are now also being followed up. Half of those on the high dose achieved top scores in tests that involved completing a mobility course in varying light levels. And of the 9 who received the maximum dosage, 2 had a 10,000-fold improvement in their vision.

“Although we had previously anticipated a large potential for vision improvement in Lca1, we did not know how receptive the patients’ photoreceptors would be to the treatment after decades of blindness,” Cideciyan notes. “It is very satisfying to see a successful multicenter trial showing that gene therapy can be remarkably effective.” Patients were enrolled at both the University of Pennsylvania and Oregon Health and Science University. Primarily, the study sought to determine the safety of the gene therapy and its different dose levels. Side effects were largely limited to surgical complications. The gene therapy itself caused mild inflammation that was treated with steroids.

Researchers expect the gene therapy to last indefinitely, requiring only a single treatment per eye. So far, vision improvements have been seen lasting at least 5 years. This study was funded by Atsena Therapeutics, a University of Florida spin-off that developed the gene therapy and funded the study. “These results pave the way for the therapy to advance into a Phase 3 clinical trial and eventually be commercialized,” said Shannon Boye, who is the University’s chief of the Division of Cellular Therapy, a co-author of the study, and a co-founder of Atsena Therapeutics.

Boye has been working to develop a gene therapy targeting Lca1 for more than 20 years, since she enrolled as a graduate student at the University of Florida in 2001. Working with her husband, Sanford Boye, her lab developed the virus-based delivery system needed to deliver working copies of the Gucy2d gene into the right cells in the eyes. The Boyes founded Atsena Therapeutics in 2019 to bring the treatment and other gene therapies to market. “Most drug companies aren’t interested in treating these rare diseases because they’re not big revenue generators,” Sanford Boye said. “But we think these patients deserve attention because we have treatments that work and provide really meaningful improvements in their quality of life.” Broad access to the therapy will require FDA approval, which could come after a phase 3 clinical trial in a larger patient population.