The vision of people with a rare inherited condition that causes them to lose much of their sight in childhood was 100 to 10,000 times better after they received gene therapy in a clinical trial.
Researchers from the University of Pennsylvania, who co-led the clinical trial published in The Lancet,1 said a10,000-fold improvement in vision, achieved by patients on the highest doses, “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”.
Lead author, Dr Artur Cideciyan, a Research Professor of Ophthalmology said: “One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.”2
A total of 15 people participated in the Phase 1/2 trial, including three paediatric 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.
The trial tested different dosage levels (low, mid, and high) of the gene therapy, ATSN-101, which was adapted from the AAV5 microorganism and was surgically injected under the retina.
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 paediatric cohort of three, again after safety reviews of the previous cohorts.
“It is very satisfying to see a successful multi-centre trial that shows gene therapy can be dramatically efficacious.”
Rapid Vision Improvements
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 Dr Cideciyan. “It is very satisfying to see a successful multi-centre trial that shows gene therapy can be dramatically efficacious.”
Researchers did find some patients had side effects, but the overwhelming majority were related to the surgical procedure itself and no serious side effects were related to the study drug.
References
- Yang P, Pardon LP, Cideciyan AV, et al. 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, The Lancet. 2024; 404(10456):962-970.
- University of Pennsylvania School of Medicine, 100x improvement in sight seen after gene therapy trial (media release) 5 Sept 2024, available at: https://www.eurekalert.org/news-releases/1056835 [accessed 18 Sept 2024].