Clinical researchers at the Center for Hereditary Retinal Degenerations, Scheie Eye Institute, University of Pennsylvania, Philadelphia, have published the results of a Phase 1/2 study in The Lancet (Vol. 404 Sep. 7th, 2024), showing clinically significant improvements in retinal sensitivity with a AAV5 gene therapy for LCA 1 patients, diagnosed by mutations in GUCY2D, on chromosome 17p13.1. Leber congenital amaurosis (LCA) is among the most severe IRD pathologies known, arising from over 20 separate genes. While LCA2 (due to mutations in RPE65) is well known due to the approval of voretigene neparvovec-rzl(Luxturna) in 2017, LCA1 was the first gene linked to Leber congenital amaurosis and causes up to 20% of cases. LCA1 disease arises from variants by the gene retinal guanylyl cyclase 1 (RETGC-1), a protein expressed in photoreceptors that facilitates phototransduction by re-synthesising the cyclic guanosine monophosphate required to return photoreceptors to a dark-adapted state following light exposure. Best-corrected visual acuity (BCVA) with LCA1 patients typically range from 20/80 to no light perception however, OCT appears relatively well preserved with a largely intact retinal structure allowing an experimental therapy to restore functional RETGC-1 and potentially improve vision.
In the current Phase 1/2 study, fifteen patients were recruited with genetically confirmed biallelic mutations in GUCY2D receiving unilateral subretinal injections of “ATSN-101” – a recombinant adeno-associated virus serotype 5 (AAV5) vector containing the human GUCY2D cDNA under the transcriptional control of the human rhodopsin kinase (hGRK1) promoter. The study used a dose-escalation phase, three adult cohorts (n=3 each) treated with three ascending doses: 1.0 × 10¹⁰ vg/eye (low dose), 3.0 × 10¹⁰ vg/eye (middle dose), and 1.0 × 10¹¹ vg/eye (high dose). In the dose-expansion phase, one adult cohort (n=3) and one paediatric cohort (n=3) were treated at the high dose. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and secondary endpoints included full-field stimulus testing (FST) and BCVA. A multi-luminance mobility test (MLMT) was also performed for the study, similar to the mobility test that was approved by FDA for voretigene neparvovec-rzl. For patients who received the ATSN-101 high dose, the mean change in dark adapted FST was 20.3 decibels (dB; 95% CI 6.6 to 34.0) for treated eyes and 1.1 dB (–3.7 to 5.9) for untreated eyes at month 12 (white stimulus); improvements were first observed at day 28 and persisted over 12 months (p=0.012). Modest improvements in BCVA were also observed (p=0.10). There were a total of 68 TEAEs (treatment-emergent adverse events) observed, 56 of which were related to the surgical procedure and there was no serious TEAE related to the study drug. The treatment, sponsored by Atsena Therapeutics, previously published a summary data outcome on FST:
Figure 1: Changes in dark-adapted FST are shown for patients who received the high dose (cohorts 3–5, n=9) in response to a white stimulus (DA), a blue stimulus (DB), and a red stimulus (DC). *: p<0.05, **: p<0.01 from paired t-test; error bars represent mean +/- standard error. Eyes treated at the high dose (1.0 × 1011 vg/eye) are shown in red, and untreated eyes are shown in blue. Treated eyes showed significant improvements in FST for all stimulus colours. (https://www.atsenatx.com/wp-content/uploads/2024/02/MaculaSociety2024Feb.pdf).
In addition to FST, the study reported a mean change in BCVA over time for patients receiving the high dose of ATSN-101 (cohorts 3–5, n=9). Eyes treated at this high dose (1.0 × 10¹¹ vg/eye) measured as a −0.16 improvement in logMAR, which translates almost two lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Commenting on the work, the lead author Artur V. Cideciyan PhD, Research Professor of Ophthalmology at the Scheie Eye Institute of the University of Pennsylvania, stated that, “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. It is very satisfying to see a successful multi-center trial that shows gene therapy can be dramatically efficacious.” Following the publication at The Lancet, the authors concluded that, “ATSN-101 has the potential to be a first-in-class treatment for LCA1, a blinding condition with no approved treatment. The favourable safety profile and improvements in retinal sensitivity observed in this phase 1/2 clinical trial are supportive of a future randomised, controlled phase 3 trial to further investigate the efficacy and safety of this novel subretinal gene therapy.”
Figure 2: Photo of Artur Cideciyan, PhD, Research Professor of Ophthalmology at the Scheie Eye Institute of the University of Pennsylvania