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A subretinal gene therapy was well tolerated 1 year after treatment, with no drug-related serious adverse events, in a small group of patients with Leber congenital amaurosis 1 (LCA1), a rare inherited retinal disorder that causes blindness in early childhood, a phase I/II study suggested.

Among the 15 adults and children with LCA1, which is caused by mutations in GUCY2D, 68 treatment-emergent adverse events (TEAEs) were observed with three different doses of unilateral subretinal injections of ATSN-101, 56 of which were related to the procedure, reported Paul Yang, MD, of the Casey Eye Institute at Oregon Health & Science University in Portland, and colleagues in .

There were no serious TEAEs related to the study drug, and ocular inflammation was mild and reversible with steroid treatment, they noted.

In the second part of the trial in which patients received the highest dose of ATSN-101, mean change in dark-adapted full-field stimulus test (FST) was 20.3 decibels (dB; 95% CI 6.6-34.0) for treated eyes and 1.1 dB (95% CI -3.7 to 5.9) for untreated eyes at month 12 (white stimulus). Improvements were first observed at day 28 and persisted over 1 year (P=0.012). In addition, modest, but not significant, improvements in best-corrected visual acuity (BCVA) were also observed (P=0.10).

"Some of the effects are so large that they are mind-boggling," co-author Artur Cideciyan, PhD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, told MedPage Today.

Another co-author, Kenji Fujita, MD, chief medical officer of study funder Atsena Therapeutics in Durham, North Carolina, elaborated on these effects, noting that "some examples include a patient seeing a star for the first time, a patient being able to read food labels for the first time, and a patient who could see lines in the crosswalk at night for the first time. We even had one patient's mother provide video of her seeing snowflakes for the first time."

LCA1 only affects about two to three out of every 100,000 people, Fujita said. "It typically presents in early childhood. Severity varies from patient to patient, but most patients are legally blind from a very young age."

According to Cideciyan, patients often have uncontrollable eye movements and reduced fields of vision. In general, they have reduced sensitivity to light, he noted. "They require more light than usual, and then when the light level drops below that, they become completely blind."

No treatment exists for LCA1. There is an approved gene therapy for another form of LCA caused by mutations in RPE65, voretigene neparvovec (Luxturna), which is listed at . The researchers declined to speculate about how much the study drug will cost. However, "it's somewhat predictable that it will be expensive," Cideciyan said.

ATSN-101 is delivered via a virus that's injected under the retina. The virus "contains a healthy copy of the GUCY2D gene," Fujita said, and "delivers that normal copy of GUCY2D to photoreceptors and restores their function. Once their function is restored, the retina can respond to light, and the patient's vision is improved."

Improved vision among these patients has persisted since the 2019-2022 study, Cideciyan said, noting that almost all gene therapies are designed to be one-time treatments.

However, there are still questions about the treatment, he added. "Forms of genetic blindness are usually progressive. Over years to decades, there is loss of cells, and when the cells are lost, their function is lost. We are not sure whether we are affecting that. What we do know is that in the short term, we're able to improve the function of the cells that are there."

In an , Robert MacLaren, MBChB, DPhil, of the University of Oxford in England, wrote that "successful gene replacement in rods should ... lead to lasting preservation of the retinal structure since rods are the predominant cell type that make up the structure of the retina outside of the fovea. In turn, this should lead to preservation of cone photoreceptors and hence visual acuity in participants treated even in later stages of vision loss."

For this multicenter, open-label, unilateral dose escalation study, Yang and colleagues treated adult cohorts of three patients each in the worse-seeing eye with three ascending doses of 1.0 × 10¹⁰ vg/eye, 3.0 × 10¹⁰ vg/eye, and 1.0 × 10¹¹ vg/eye of ATSN-101, a recombinant adeno-associated virus serotype 5 (AAV5) vector containing the human GUCY2D cDNA. Three adults and three children were then treated at the highest dose in the dose-expansion phase.

The primary endpoint was the incidence of TEAEs, with conjunctival hemorrhage (87%), ocular discomfort (80%), and hypotony of eye (53%) being the most common. Secondary endpoints included the FST and BCVA.

A multi-luminance mobility test (MLMT) was also done, and three of six patients who received the high dose and did the MLMT achieved the maximum score of 6 in the treated eye, indicating the dimmest level was passed (a minimum score of -1 indicates no level was passed).

"We will be meeting with the FDA later this year to discuss our findings and to gain agreement on next steps, which will include a larger phase III trial, followed by an application for approval," Fujita said. "We haven't yet publicly shared anticipated timelines."

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