Gene therapy is showing promising results in restoring vision for individuals with Leber congenital amaurosis type 1 (LCA1), a rare genetic form of blindness. A Phase 1/2 clinical trial evaluating ATSN-101, a gene therapy developed by Atsena Therapeutics, demonstrated significant and durable improvements in vision for patients with LCA1, offering hope for a potential treatment for this currently untreatable condition.
Vision Improvements
The study, published in The Lancet, involved 15 patients with LCA1 caused by mutations in the GUCY2D gene. The results showed that some patients experienced a remarkable 10,000-fold increase in light sensitivity after receiving the highest dose of ATSN-101. This level of improvement allowed them to see in environments as dim as a moonlit night, a stark contrast to their previous reliance on bright indoor lighting.
Artur Cideciyan, PhD, Research Professor of Ophthalmology at the Scheie Eye Institute of the University of Pennsylvania and senior author of the paper, noted, "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. One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire."
Study Design and Results
The Phase 1/2 trial was designed as a multi-center, open-label, unilateral dose-escalation study. Patients received a subretinal injection of ATSN-101 in one eye. The trial included three dose levels: low, medium, and high. Researchers assessed the safety and efficacy of the gene therapy over a 12-month period.
The primary endpoint of the trial was the incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included changes in full-field stimulus test (FST) and best-corrected visual acuity (BCVA). A multi-luminance mobility test (MLMT) was also performed to assess functional vision improvements.
Results indicated that the high-dose group experienced a mean change in dark-adapted FST of 20.3 decibels, representing a 100-fold improvement for treated eyes (p = 0.012). Modest improvements in BCVA were also observed, with an average improvement of -0.16 logMAR or 8 letters 12 months post-treatment for high-dose subjects (p = 0.10). Three of six high-dose subjects achieved the maximum score on the MLMT in the treated eye at Month 12.
Safety and Tolerability
The gene therapy demonstrated a favorable safety profile. Most adverse events were mild (91%) or moderate (9%) in severity and were related to the surgical procedure. Ocular inflammation was mild and reversible with steroid treatment. No serious TEAEs were related to ATSN-101.
Future Directions
The promising results from this Phase 1/2 trial support the advancement of ATSN-101 into a Phase 3 clinical trial. This larger, randomized, controlled trial will further evaluate the efficacy and safety of the gene therapy in a broader population of LCA1 patients.
Kenji Fujita, MD, Chief Medical Officer of Atsena Therapeutics, stated, "The preliminary efficacy and robust safety data from our ongoing Phase I/II trial underscore the potential of ATSN-101 to be a first-in-class gene therapy for LCA1. It is encouraging that improvements in retinal sensitivity were observed as early as 28 days post-treatment and persisted over at least 12 months, highlighting the durability of our investigational gene therapy."
About LCA1
Leber congenital amaurosis type 1 (LCA1) is a rare inherited retinal disease caused by biallelic mutations in the GUCY2D gene. It leads to severe vision impairment or blindness in infancy or early childhood. Currently, there are no approved treatments for LCA1, highlighting the significant unmet medical need for this patient population. It affects roughly 20 percent of patients who live with this group of inherited retinal diseases.
About ATSN-101
ATSN-101 is an investigational, subretinal AAV5 gene therapy designed to deliver a functional copy of the human GUCY2D gene to photoreceptors in the eye. It has received Rare Pediatric Disease designation, Regenerative Medicine Advanced Therapy designation, and Orphan Drug designation from the U.S. Food and Drug Administration for the treatment of GUCY2D-associated LCA1.
