Recovery of cone-mediated vision in Lebercilin associated retinal ciliopathy after gene therapy: One-year results of a phase I/II trial

Abstract

We assessed the preliminary safety of a recombinant adeno-associated virus serotype 8 vector carrying the native human LCA5 cDNA (OPGx-001) in LCA5-associated Leber congenital amaurosis (LCA5-LCA), a congenital blindness. This phase 1b/2a trial (NCT05616793) is a nonrandomized, single ascending, dose-escalation study. Three subjects with LCA5-LCA (ages 19, 26, and 34 years old) received uniocular subretinal injections of 1E10 vector genome per eye of OPGx-001. There were no serious adverse events related to OPGx-001 or the procedure. Retinal microstructure by spectral-domain optical coherence tomography showed no major changes in retinal lamination of the treated central retina compared with the contralateral control. Efficacy was detectable in these severely affected patients by subjective and objective methods at 1-month post-treatment and persisted for at least 12 months. Chromatic full-field stimulus testing showed improvements in cone-mediated vision averaging ∼1 log₁₀ unit. Objective pupillometry confirmed perceptual results. Improvements were associated with better performance on a virtual reality orientation and mobility test. Visual acuity returned to baseline or improved in the treated eyes of all participants. The favorable safety profile and efficacy outcomes pave the path for enrolling milder phenotypes with careful dose escalation.

Keywords: AAV8; LCA5; Leber congenital amaurosis; Lebercilin.

Graphical abstract

Figure 1

Improvement in cone-mediated vision in gene therapy-treated eyes of patients with LCA5-LCA (A) Raw FST data with red stimuli recorded at baseline (BL) and month 12 (M12) in control and study eyes of the study participants under dark-adapted (DA) or light-adapted (LA) conditions. Mean proportions seen (symbols) are fit with a modified Weibull function (smooth curves). Threshold is estimated at 50% seen (vertical dashed lines ending in down-pointing triangle near abscissa). (B) All individual FST threshold estimates (smaller symbols) and mean ± SEM (larger symbols) across time shown normalized by average baseline thresholds and thus expressed as changes from baseline. Horizontal gray dashed line represents no change from baseline. (C) Interocular differences (study eye minus control eye) in FST thresholds over time. Horizontal gray dashed line represents the pre-treatment interocular difference favoring the control eyes. Directions of better or worse vision, and improvement of vision over time shown along the abscissa (A) and ordinates (B and C) with arrows.

Figure 2

Objective changes in vision measured by dark-adapted pupillary light reflexes (A) Non-linear functions (lines) best fit to pupillary response contraction amplitudes (symbols) measured at 0.9 s after the onset of 1-s-long red stimuli presented to dark-adapted eyes. Thicker gray lines are functions fit to pre-treatment datasets, thinner black and green lines represent post-treatment time points in control and study eyes, respectively. (B and C) Pupillary response threshold (B) and latency (C) to a 0.3-mm criterion pupillary response expressed as change from baseline (CFB) average pre-treatment values. Individual estimates (smaller symbols) and mean ± SEM (larger symbols) across time are shown. Directions of better or worse vision, and improvement of vision over time are shown along the abscissa (A) and ordinates (B and C) with arrows.

Figure 3

Changes in visual acuity post-treatment (A) All individual visual acuity (VA) estimates (smaller symbols) and mean ± SEM (larger symbols) across time are shown normalized by average baseline thresholds and expressed as changes from baseline (CFBs). Horizontal dashed gray line represents no change from baseline. (B) Interocular differences (study eye minus control eye) in VA over time. Horizontal dashed gray line represents the pre-treatment interocular difference. Directions of improvement and better vision over time are shown with arrows.

Figure 4

Impact on foveal and spatial vision after gene augmentation (A) Retinal sensitivity (left panels) and fixation location and stability (right panels) in the control and study eyes of subject 01–04 determined by retina-tracked perimetry at baseline, 1 month (1M) and 12 months (12M) post-treatment. Sensitivities are measured using a 0.45-degree diameter white target presented on a white mesopic background at 68 central retinal locations on a standard 10-2 visual field protocol pattern. Sensitivity values (in dB) at each location are shown next to symbols colored using a reference sensitivity scale (bottom, maximal), superimposed on a near infrared reflectance image of the central retina; size scales shown at the bottom. The fraction shown in green at the location of the optic nerve represents the number of perceived stimuli over the number of presentations at that location using the maximal luminance of the stimuli, a measure of the false positive rate (or button presses when the subject should not have perceived the stimulus, considered reliable if <33%). Fixation stability and location over time are represented by a cloud of green dots. Bivariate contour ellipse areas (BCEA) automatically fit by the instrument’s software delineate the retinal area used for fixation by 63% (inner) and 95% (outer ellipse) of the fixation points recorded during the microperimetry test. (B) Chromatic visual acuities in subject 01–04 measured using red-on-blue (left) and blue-on-yellow (left) gratings (colored insets) expressed as change from baseline (CFB, top panels) and as interocular differences (IODs, study eye minus control eye; bottom panels). Horizontal dashed gray lines represent no change from baseline, directions of improvement of vision or eye with better vision are shown to the right.

Figure 5

Functional vision assessments using a virtual reality orientation and mobility test (A) Counts of identified objects tested under monocular testing for each visit (filled symbols) compared with average performance in healthy subjects (unfilled circles, error bars are ±2 SEM). Each symbol is the average of at least two repetitions performed. (B) Summary of changes from baseline (CFBs) in the correctly identified objects at the luminance level of −1.2 log phot-cd.m⁻². Reported (Bennett et al. 2022⁵⁷) test-retest variability (mean ± 2 SD) is shown (dashed lines). Directions of improvement of vision shown below.