Gene Therapy Shows Promise in Leber Congenital Amaurosis


Significant improvements were reported in full-field stimulus testing.

Atsena Therapeutics’ ATSN-101 (previously referred to as SAR439483), an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat Leber Congenital Amaurosis caused by biallelic mutations in GUCY2D (LCA1), has demonstrated promising safety and efficacy in a phase 1/2 clinical trial (NCT03920007), according to data presented at the American Academy of Ophthalmology (AAO) annual meeting which took place from September 30 – October 1, 2022, in Chicago, Illinois.1,2

ATSN-101 utilizes an AAV5 capsid and is delivered via subretinal injection. It is intended to provide photoreceptors with a functional copy of GUCY2D, the disease-targeted gene. Among the patients treated with the highest dose in the trial, significant improvement was reported in full-field stimulus testing (FST) across the 3 colors that were tested with dark adapted FST. Clinically meaningful improvements in multi-luminance mobility testing (MLMT) were reported in 3 of 4 participants tested. In terms of safety, no therapy-related serious adverse events (SAEs) were reported. Two cases of ocular inflammation were reported, both being grade 2 and resolving with administration of steroid treatment.

“[I]mportantly, [the majority of patients with LCA1] have a normal retinal thickness,” presenter Christine Nichols Kay, MD, Atsena Therapeutics, said during her presentation.1 “We can see preserved photoreceptor structure and this does increase the odds of success with retinal gene therapy.”

The ages of the 15 patients who were treated in the clinical trial ranged from 12 years to 76 years (median, 21). The group included 10 female patients and 5 male patients, and racial demographics included 67% white patients and 20% Asian patients, with the race of the remaining patients unreported. The baseline median best corrected visual acuity (BCVA) (logMAR) in the study eye ranged from 0.72 to 4 (median, 1.32).  Patients were required to have the outer nuclear layer identifiale on central retina optical coherence tomography in order to be included in the study.

The patients were divided across 5 cohorts, each of which contained 3 patients. The first 3 cohorts (20/200 BCVA or worse) were treated in the dose escalation phase, with cohort 1 receiving a dose of 1.0x1010 vg/eye of ATSN-101, cohort 2 receiving a dose of 3.0x1010 vg/eye, and cohort 3 receiving 1.0x1011 vg/eye. All patients in these cohorts were older than 18 years of age. The 1.0x1011 vg/eye dose was selected for the expansion phase (BCVA 20/80 or worse), which treated patients older than 18 years in cohort 4 and patients aged 18 years and younger in cohort 5.

“Interestingly, there was [a] 76-year-old in this trial and this patient actually did quite well with a robust FST improvement signal,” Kay added in the presentation.1

The BCVA response among the patients treated was variable. However, all 4 patients tested with Spark Therapeutics' MLMT, all of whom received the highest dose, showed either an improvement to the maximum MLMT score of 6 (n=1) or an improvement of greater than 2 levels (n=3). These improvements were compared to baseline when possible and to the untreated eye when baseline data were unavailable.

All 3 SAEs reported were related to the surgical procedure and included a macular hole in one patient and endopthalmitis and retinal detachment in another patient. The 2 cases of ocular inflammation mentioned above included a case of subretinal inflammation and a case of vitritis. Kay noted that the 2 patients who experienced these cases of ocular inflammation still showed FST improvements. In total, 56 treatment-emergent AEs were reported, and 52 of these were related to the surgical procedure. No patients dropped out of the study due to AEs.

1. Kay CN, Yang P, Cideciyan A, et al. Safety and Efficacy of SAR439483 in Patients with Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D (LCA1). Presented at: AAO annual meeting. September 30 – October 1, 2022; Chicago, Illinois.
2. Atsena Therapeutics announces late-breaker presentation at the American Academy of Ophthalmology 2022 Annual Meeting. News release. Atsena Therapeutics. September 21, 2022.
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