Gene therapy restores vision in first-ever trial for rare, inherited blindness
Patients born with a certain genetic blindness experienced the world in an entirely new way after a single treatment with gene therapy developed at UF.
University of Florida
After the treatment, one patient saw her first star. Another saw snowflakes for the first time. Other patients were newly able to navigate outside of the home or to read the labels on their child’s Halloween candy.
The cause of these seemingly miraculous improvements? A gene therapy developed by University of Florida scientists, which restored useful vision to most patients with the rare, inherited blindness known as Leber congenital amaurosis type I, or LCA1, in a small trial.
Those who received the highest dose of the gene therapy saw up to a 10,000-fold improvement in their light sensitivity, were able to read more lines on an eye chart, and improved in their ability to navigate a standardized maze. For many patients, it was akin to finally turning on dim lights after trying to navigate their homes in the pitch black for years, the researchers said.
The trial also tested the safety profile of the treatment. Side effects were largely limited to minor surgical complications. The gene therapy itself caused mild inflammation that was treated with steroids.
“This is the first time that anyone with LCA1 has ever been treated, and we showed a very clean safety profile, and we also showed efficacy. These results pave the way for advancing the therapy in a phase 3 clinical trial and eventually commercializing it,” said Shannon Boye, Ph.D., chief of the Division of Cellular and Molecular Therapy at UF, co-author of the study and co-founder of Atsena Therapeutics, the UF spinoff that developed the gene therapy and funded the study.
“Atsena is pleased to advance the foundational work that Shannon and Sanford Boye developed in their laboratory many years ago and thrilled that the 12-month data from our ongoing clinical trial have been published in a prestigious medical journal,” said Kenji Fujita, M.D., chief medical officer of Atsena Therapeutics and co-author of the study. “We look forward to sharing further results from this program as we continue progressing what has the potential to be a breakthrough in treating blindness in children and adults with LCA1.”
Shannon Boye, UF professor of pediatrics and Sanford Boye, associate scientist of pediatrics, and their collaborators at the University of Pennsylvania and Oregon Health and Science University published the results of the clinical trial Sept. 5 in the journal The Lancet.
LCA1 is rare. Only about 3,000 people have the condition across both Europe and the U.S. It is caused by having two defective copies of the gene GUCY2D, which is required for the light-sensitive cells in the eyes to function properly. People with the disease tend to have severely impaired vision that makes it difficult or impossible to drive, read, or navigate the world visually.
Shannon Boye has been developing the gene therapy targeting LCA1 for more than 20 years, since she enrolled as a graduate student at UF in 2001. In collaboration with her husband Sanford Boye, Shannon Boye’s lab developed the virus-based transport system that is essential for delivering functioning copies of the GUCY2D gene into the correct cells in the eyes. The Boyes founded Atsena Therapeutics in 2019 to bring the LCA1 treatment and other gene therapies to market.
“Most pharmaceutical companies are not interested in treating these rare diseases, because they are not strong revenue generators,” Sanford Boye said. “But we think these patients deserve attention, because we have treatments that work and provide really meaningful improvements to their quality of life.”
The study enrolled 15 subjects for treatment at the University of Pennsylvania or Oregon Health and Science University. Subjects received one of three different doses of the therapy to identify the safest and most effective dose for future trials. All patients received the treatment in one eye, which involved a surgical injection in the retina.
Researchers followed the patients for a year to test their vision in the treated eye compared to the untreated eye. Subjects who received higher doses saw greater improvements in their vision.
The researchers expect the gene therapy to last indefinitely, requiring just a single treatment per eye. So far, they have seen visual improvements last at least five years.
Broad access to the treatment will require approval by the FDA following a phase 3 clinical trial, which tests the therapy in a larger population of patients.
Journal
The Lancet
Method of Research
Randomized controlled/clinical trial
Subject of Research
People
Article Title
Safety and Efficacy of ATSN-101 in Patients with Leber Congenital Amaurosis caused by Biallelic Mutations in GUCY2D: A Phase 1/2, Multi-Center, Open-Label, Unilateral Dose Escalation Study
Article Publication Date
5-Sep-2024
100x improvement in sight seen after gene therapy trial
Patients with a rare inherited disease affecting their sight experienced quick vision improvements that sustained for the full year-long study
University of Pennsylvania School of Medicine
PHILADELPHIA— The vision of people with a rare inherited condition that causes them to lose much of their sight early in childhood was 100 times better after they received gene therapy to address the genetic mutation causing it. Some patients even experienced a 10,000-fold improvement in their vision after receiving the highest dose of the therapy, according to researchers from the Perelman School of Medicine at the University of Pennsylvania who co-led the clinical trial published in The Lancet.
“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 the study’s lead author, Artur Cideciyan, PhD, a research professor of Ophthalmology and co-director of the Center for Hereditary Retinal Degenerations. “One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.”
A total of 15 people participated in the Phase 1/2 trial, including three pediatric patients. Each patient had Leber congenital amaurosis as the result of mutations in the GUCY2D gene, which is essential to producing proteins critical for vision. This specific condition, which affects less than 100,000 people worldwide and is abbreviated as LCA1, causes significant amount of vision loss as early as infancy.
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. Glasses provide limited benefit to these patients because they correct abnormalities in the optical focusing ability of the eye, and are unable to address medical causes of vision loss, such as genetic retinal diseases like LCA1.
The trial tested different dosage levels of the gene therapy, ATSN-101, which was adapted from the AAV5 microorganism and 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. Evaluations were held between each level of dosage to ensure that they were safe before upping the dosage for the next cohort. 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, again after safety reviews of the previous cohorts.
Improvements were noticed quickly, often within the first month, after the therapy was applied and lasted for at least 12 months. Observations of participating patients are also 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 the 10,000-fold improvement in vision.
“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.”
Primarily, the study sought to determine the safety of the gene therapy and its varying dosage levels. Researchers did find some patients had side effects, but the overwhelming majority 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. No serious side effects were related to the study drug.
This work comes on the heels of another successful ophthalmological trial at Penn 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. Co-led by one of the new paper’s co-authors, Tomas S. Aleman, MD, the Irene Heinz-Given and John LaPorte Research Professor in Ophthalmology and co-director with Cideciyan of the Center for Hereditary Retinal Degenerations, the study used similar tests and 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 percent of infantile blindness caused by inherited retinal degenerations,” Aleman said. “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.”
Moving forward, approval of this experimental medicine for clinical use requires another trial, where participants are randomized to a treatment dose and both patients and those investigating the trial not knowing who gets what. Through that, any possible bias in results could be avoided.
This study was funded by Atsena Therapeutics, Inc. Two of the paper’s authors, Andres K. Lauer, MD, and Mark Pennesi, MD, PhD, are members of the company’s clinical and scientific advisory board.
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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.
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Journal
The Lancet
Article Title
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
Article Publication Date
5-Sep-2024
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