Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study.

BACKGROUND: Leber congenital amaurosis 1 (LCA1), caused by mutations in GUCY2D, is a rare inherited retinal disease that typically causes blindness in early childhood. The aim of this study was to evaluate the safety and preliminary efficacy of ascending doses of ATSN-101, a subretinal AAV5 gene therapy for LCA1. METHODS: 15 patients with genetically confirmed biallelic mutations in GUCY2D were included in this phase 1/2 study. All patients received unilateral subretinal injections of ATSN-101. In the dose-escalation phase, three adult cohorts (n=3 each) were 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 test (FST) and best-corrected visual acuity (BCVA). A multi-luminance mobility test (MLMT) was also done. Data through the 12-month main study period are reported. FINDINGS: Patients were enrolled between Sept 12, 2019, and May 5, 2022. A total of 68 TEAEs were observed, 56 of which were related to the surgical procedure. No serious TEAE was related to the study drug. Ocular inflammation was mild and reversible with steroid treatment. For patients who received the high dose, 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). Three of six patients who received the high dose and did the MLMT achieved the maximum score in the treated eye. INTERPRETATION: ATSN-101 is well tolerated 12 months after treatment, with no drug-related serious adverse events. Clinically significant improvements in retinal sensitivity were sustained in patients receiving the high dose. FUNDING: Atsena Therapeutics.

Mobility test to assess functional vision in dark-adapted patients with Leber congenital amaurosis.

BACKGROUND: Inherited retinal degenerations (IRDs) affect daylight and night vision to different degrees. In the current work, we devise a method to quantify mobility under dark-adapted conditions in patients with severe childhood blindness due to Leber congenital amaurosis (LCA). Mobility thresholds from two different LCA genotypes are compared to dark-adapted vision measurements using the full-field stimulus test (FST), a conventional desktop outcome measure of rod vision. METHODS: A device consisting of vertical LED strips on a plane resembling a beaded curtain was programmed to produce a rectangular pattern target defining a 'door' of varying luminance that could appear at one of three positions. Mobility performance was evaluated by letting the subject walk from a fixed starting position ~ 4 m away from the device with instructions to touch the door. Success was defined as the subject touching within the 'door' area. Ten runs were performed and the process was repeated for different levels of luminance. Tests were performed monocularly in dark-adapted and dilated eyes. Results from LCA patients with the GUCY2D and CEP290 genotypes and normal subjects were analyzed using logistic regression to estimate the mobility threshold for successful navigation. The relation of thresholds for mobility, FST and visual acuity were quantified using linear regression. RESULTS: Normal subjects had mobility thresholds near limits of dark-adapted rod vision. GUCY2D-LCA patients had a wide range of mobility thresholds from within 1 log of normal to greater than 8 log abnormal. CEP290-LCA patients had abnormal mobility thresholds that were between 5 and 6 log from normal. Sensitivity loss estimates using FST related linearly to the mobility thresholds which were not correlated with visual acuity. CONCLUSIONS: The mobility task we developed can quantify functional vision in severely disabled patients with LCA. Taken together with other outcome measures of rod and cone photoreceptor-mediated vision, dark-adapted functional vision should provide a more complete understanding of the natural history and effects of treatment in patients with LCA.

Leber Congenital Amaurosis Due to GUCY2D Mutations: Longitudinal Analysis of Retinal Structure and Visual Function.

Gene augmentation therapy is being planned for GUCY2D-associated Leber congenital amaurosis (LCA). To increase our understanding of the natural history of GUCY2D-LCA, patients were evaluated twice with an interval of 4 to 7 years between visits using safety and efficacy outcome measures previously determined to be useful for monitoring this disorder. In this group of molecularly-identified LCA patients (n = 10; ages 7-37 years at first visit), optical coherence tomography (OCT) was used to measure foveal cone outer nuclear layer (ONL) thickness and rod ONL at a superior retinal locus. Full-field stimulus testing (FST) with chromatic stimuli in dark- and light-adapted states was used to assay rod and cone vision. Changes in OCT and FST over the interval were mostly attributable to inter-visit variability. There were no major negative changes in structure or function across the cohort and over the intervals studied. Variation in severity of disease expression between patients occurs; however, despite difficulties in quantifying structure and function in such seriously visually impaired individuals with nystagmus, the present work supports the use of OCT as a safety outcome and FST as an efficacy outcome in a clinical trial of GUCY2D-LCA. A wide age spectrum for therapy was confirmed, and there was relative stability of structure and function during a typical time interval for clinical trials.

Short-Wavelength Sensitive Cone (S-cone) Testing as an Outcome Measure for NR2E3 Clinical Treatment Trials.

Recessively-inherited NR2E3 gene mutations cause an unusual retinopathy with abnormally-increased short-wavelength sensitive cone (S-cone) function, in addition to reduced rod and long/middle-wavelength sensitive cone (L/M-cone) function. Progress toward clinical trials to treat patients with this otherwise incurable retinal degeneration prompted the need to determine efficacy outcome measures. Comparisons were made between three computerized perimeters available in the clinic. These perimeters could deliver short-wavelength stimuli on longer-wavelength adapting backgrounds to measure whether S-cone vision can be quantified. Results from a cohort of normal subjects were compared across the three perimeters to determine S-cone isolation and test-retest variability. S-cone perimetry data from NR2E3-ESCS (enhanced S-cone syndrome) patients were examined and determined to have five stages of disease severity. Using these stages, strategies were proposed for monitoring efficacy of either a focal or retina-wide intervention. This work sets the stage for clinical trials.

Photoreceptor function and structure in retinal degenerations caused by biallelic BEST1 mutations.

The only approved retinal gene therapy is for biallelic RPE65 mutations which cause a recessive retinopathy with a primary molecular defect located at the retinal pigment epithelium (RPE). For a distinct recessive RPE disease caused by biallelic BEST1 mutations, a pre-clinical proof-of-concept for gene therapy has been demonstrated in canine eyes. The current study was undertaken to consider potential outcome measures for a BEST1 clinical trial in patients demonstrating a classic autosomal recessive bestrophinopathy (ARB) phenotype. Spatial distribution of retinal structure showed a wide expanse of abnormalities including large intraretinal cysts, shallow serous retinal detachments, abnormalities of inner and outer segments, and an unusual prominence of the external limiting membrane. Surrounding the central macula extending from 7 to 30 deg eccentricity, outer nuclear layer was thicker than expected from a cone only retina and implied survival of many rod photoreceptors. Co-localized however, were large losses of rod sensitivity despite preserved cone sensitivities. The dissociation of rod function from rod structure observed, supports a large treatment potential in the paramacular region for biallelic bestrophinopathies.

Color Vision in Blue Cone Monochromacy: Outcome Measures for a Clinical Trial.

Purpose: Blue cone monochromacy (BCM) is an X-linked retinopathy due to mutations in the OPN1LW/OPN1MW gene cluster. Symptoms include reduced visual acuity and disturbed color vision. We studied BCM color vision to determine outcome measures for future clinical trials. Methods: Patients with BCM and normal-vision participants were examined with Farnsworth-Munsell (FM) arrangement tests and the Color Assessment and Diagnosis (CAD) test. A retrospective case series in 36 patients with BCM (ages 6-70) was performed with the FM D-15 test. A subset of six patients also had Roth-28 Hue and CAD tests. Results: All patients with BCM had abnormal results for D-15, Roth-28, and CAD tests. With D-15, there was protan-deutan confusion and no bimodal tendency. Roth-28 results reinforced that finding. There was symmetry in color vision metrics between the two eyes and coherence between sessions with the arrangement tests and CAD. Severe abnormalities in red-green sensitivity with CAD were expected. Unexpected were different levels of yellow-blue results with two patterns of abnormal thresholds: moderate elevation in two younger patients and severe elevation in four patients ≥35 years. Coefficients of repeatability and intersession means were tabulated for all test modalities. Conclusions: Given understanding of advantages, disadvantages, and complexities of interpretation of results, both an arrangement test and CAD should be useful monitors of color vision through a clinical trial in BCM. Translational Relevance: Our pilot studies in BCM of arrangement and CAD tests indicated both were clinically feasible and interpretable in the context of this cone gene disease.

Durable vision improvement after a single intravitreal treatment with antisense oligonucleotide in CEP290-LCA: Replication in two eyes.

Purpose: An intravitreally injected antisense oligonucleotide, sepofarsen, was designed to modulate splicing within retinas of patients with severe vision loss due to deep intronic c.2991 + 1655A > G variant in the CEP290 gene. A previous report showed vision improvements following a single injection in one eye with unexpected durability lasting at least 15 months. The current study evaluated durability of efficacy beyond 15 months in the previously treated left eye. In addition, peak efficacy and durability were evaluated in the treatment-naive right eye, and re-injection of the left eye 4 years after the first injection. Observations: Visual function was evaluated with best corrected standard and low-luminance visual acuities, microperimetry, dark-adapted chromatic perimetry, and full-field sensitivity testing. Retinal structure was evaluated with OCT imaging. At the fovea, all visual function measures and IS/OS intensity of the OCT showed transient improvements peaking at 3-6 months, remaining better than baseline at ∼2 years, and returning to baseline by 3-4 years after each single injection. Conclusions and Importance: These results suggest that sepofarsen reinjection intervals may need to be longer than 2 years.

Treatment Strategy With Gene Editing for Late-Onset Retinal Degeneration Caused by a Founder Variant in C1QTNF5.

Purpose: Genome editing is an emerging group of technologies with the potential to ameliorate dominant, monogenic human diseases such as late-onset retinal degeneration (L-ORD). The goal of this study was to identify disease stages and retinal locations optimal for evaluating the efficacy of a future genome editing trial. Methods: Twenty five L-ORD patients (age range, 33-77 years; median age, 59 years) harboring the founder variant S163R in C1QTNF5 were enrolled from three centers in the United Kingdom and United States. Patients were examined with widefield optical coherence tomography (OCT) and chromatic perimetry under dark-adapted and light-adapted conditions to derive phenomaps of retinal disease. Results were analyzed with a model of a shared natural history of a single delayed exponential across all subjects and all retinal locations. Results: Critical age for the initiation of photoreceptor loss ranged from 48 years at the temporal paramacular retina to 74 years at the inferior midperipheral retina. Subretinal deposits (sRET-Ds) became more prevalent as critical age was approached. Subretinal pigment epithelial deposits (sRPE-Ds) were detectable in the youngest patients showing no other structural or functional abnormalities at the retina. The sRPE-D thickness continuously increased, reaching 25 µm in the extrafoveal retina and 19 µm in the fovea at critical age. Loss of light sensitivity preceded shortening of outer segments and loss of photoreceptors by more than a decade. Conclusions: Retinal regions providing an ideal treatment window exist across all severity stages of L-ORD.

Full-field stimulus testing: Role in the clinic and as an outcome measure in clinical trials of severe childhood retinal disease.

Disease mechanisms have become better understood in previously incurable forms of early-onset severe retinal dystrophy, such as Leber congenital amaurosis (LCA). This has led to novel treatments and clinical trials that have shown some success. Standard methods to measure vision were difficult if not impossible to perform in severely affected patients with low vision and nystagmus. To meet the need for visual assays, we devised a psychophysical method, which we named full-field stimulus testing (FST). From early versions based on an automated perimeter, we advanced FST to a more available light-emitting diode platform. The journey from invention to use of such a technique in our inherited retinal degeneration clinic is reviewed and many of the lessons learned over the 15 years of application of FST are explained. Although the original purpose and application of FST was to quantify visual thresholds in LCA, there are rare opportunities for FST also to be used beyond LCA to measure aspects of vision in other inherited retinal degenerations; examples are given. The main goal of the current review, however, remains to enable investigators studying and treating LCA to understand how to best use FST and how to reduce artefact and confounding complexities so the test results become more valuable to the understanding of LCA diseases and results of novel interventions.

Photoreceptor Function and Structure in Autosomal Dominant Vitelliform Macular Dystrophy Caused by BEST1 Mutations.

Purpose: The purpose of this study was to evaluate rod and cone function and outer retinal structure within macular lesions, and surrounding extralesional areas of patients with autosomal dominant Best vitelliform macular dystrophy caused by BEST1 mutations. Methods: Seventeen patients from seven families were examined with dark- and light-adapted chromatic perimetry and optical coherence tomography. Subsets of patients had long-term follow-up (14-22 years, n = 6) and dark-adaptation kinetics measured (n = 5). Results: Within central lesions with large serous retinal detachments, rod sensitivity was severely reduced but visual acuity and cone sensitivity were relatively retained. In surrounding extralesional areas, there was a mild but detectable widening of the subretinal space in some patients and some retinal areas. Available evidence was consistent with subretinal widening causing slower dark-adaptation kinetics. Over long-term follow-up, some eyes showed formation of de novo satellite lesions at retinal locations that years previously demonstrated subretinal widening. A subclinical abnormality consisting of a retina-wide mild thickening of the outer nuclear layer was evident in many patients and thickening increased in the subset of patients with long-term follow-up. Conclusions: Outcome measures for future clinical trials should include evaluations of rod sensitivity within central lesions and quantitative measures of outer retinal structure in normal-appearing regions surrounding the lesions.

Night vision restored in days after decades of congenital blindness.

Signaling of vision to the brain starts with the retinal phototransduction cascade which converts visible light from the environment into chemical changes. Vision impairment results when mutations inactivate proteins of the phototransduction cascade. A severe monogenically inherited blindness, Leber congenital amaurosis (LCA), is caused by mutations in the GUCY2D gene, leading to a molecular defect in the production of cyclic GMP, the second messenger of phototransduction. We studied two patients with GUCY2D-LCA who were undergoing gene augmentation therapy. Both patients had large deficits in rod photoreceptor-based night vision before intervention. Within days of therapy, rod vision in both patients changed dramatically; improvements in visual function and functional vision in these hyper-responding patients reached more than 3 log10 units (1000-fold), nearing healthy rod vision. Quick activation of the complex molecular pathways from retinal photoreceptor to visual cortex and behavior is thus possible in patients even after being disabled and dormant for decades.

Restoration of Cone Sensitivity to Individuals with Congenital Photoreceptor Blindness within the Phase 1/2 Sepofarsen Trial.

Purpose: To understand consequences of reconstituting cone photoreceptor function in congenital binocular blindness resulting from mutations in the centrosomal protein 290 (CEP290) gene. Design: Phase 1b/2 open-label, multicenter, multiple-dose, dose-escalation trial. Participants: A homogeneous subgroup of 5 participants with light perception (LP) vision at the time of enrollment (age range, 15-41 years) selected for detailed analyses. Medical histories of 4 participants were consistent with congenital binocular blindness, whereas 1 participant showed evidence of spatial vision in early life that was later lost. Intervention: Participants received a single intravitreal injection of sepofarsen (160 or 320 µg) into the study eye. Main Outcome Measures: Full-field stimulus testing (FST), visual acuity (VA), and transient pupillary light reflex (TPLR) were measured at baseline and for 3 months after the injection. Results: All 5 participants with LP vision demonstrated severely abnormal FST and TPLR findings. At baseline, FST threshold estimates were 0.81 and 1.0 log cd/m2 for control and study eyes, respectively. At 3 months, study eyes showed a large mean improvement of -1.75 log versus baseline (P < 0.001), whereas untreated control eyes were comparable with baseline. Blue minus red FST values were not different than 0 (P = 0.59), compatible with cone mediation of remnant vision. At baseline, TPLR response amplitude and latency estimates were 0.39 mm and 0.72 seconds, respectively, for control eyes, and 0.28 mm and 0.78 seconds, respectively, for study eyes. At 3 months, study eyes showed a mean improvement of 0.44 mm in amplitude and a mean acceleration of 0.29 seconds in latency versus baseline (P < 0.001), whereas control eyes showed no significant change versus baseline. Specialized tests performed in 1 participant confirmed and extended the standardized results from all 5 participants. Conclusions: By subjective and objective evidence, intravitreal sepofarsen provides improvement of light sensitivity for individuals with LP vision. However, translation of increased light sensitivity to improved spatial vision may occur preferentially in those with a history of visual experience during early neurodevelopment. Interventions for congenital lack of spatial vision in CEP290-associated Leber congenital amaurosis may lead to better results if performed before visual cortex maturity.

Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial.

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 ( NCT03140969 ), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit-risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.

Childhood-onset genetic cone-rod photoreceptor diseases and underlying pathobiology.

Inherited retinal diseases (IRDs) were first classified clinically by history, ophthalmoscopic appearance, type of visual field defects, and electroretinography (ERG). ERGs isolating the two major photoreceptor types (rods and cones) showed some IRDs with greater cone than rod retinal dysfunction; others were the opposite. Within the cone-rod diseases, there can be phenotypic variability, which can be attributed to genetic heterogeneity and the variety of visual function mechanisms that are disrupted. Most cause symptoms from childhood or adolescence, although others can manifest later in life. Among the causative genes for cone-rod dystrophy (CORD) are those encoding molecules in phototransduction cascade activation and recovery processes, photoreceptor outer segment structure, the visual cycle and photoreceptor development. We review 11 genes known to cause cone-rod disease in the context of their roles in normal visual function and retinal structure. Knowledge of the pathobiology of these genetic diseases is beginning to pave paths to therapy.

Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report.

Leber congenital amaurosis due to CEP290 ciliopathy is being explored by treatment with the antisense oligonucleotide (AON) sepofarsen. One patient who was part of a larger cohort (ClinicalTrials.gov NCT03140969 ) was studied for 15 months after a single intravitreal sepofarsen injection. Concordant measures of visual function and retinal structure reached a substantial efficacy peak near 3 months after injection. At 15 months, there was sustained efficacy, even though there was evidence of reduction from peak response. Efficacy kinetics can be explained by the balance of AON-driven new CEP290 protein synthesis and a slow natural rate of CEP290 protein degradation in human foveal cone photoreceptors.

Safety and improved efficacy signals following gene therapy in childhood blindness caused by GUCY2D mutations.

A first-in-human clinical trial of gene therapy in Leber congenital amaurosis due to mutations in the GUCY2D gene is underway, and early results are summarized. A recombinant adeno-associated virus serotype 5 (rAAV5) vector carrying the human GUCY2D gene was delivered by subretinal injection to one eye in three adult patients with severe visual loss, nystagmus, but preserved retinal structure. Safety and efficacy parameters were monitored for 9 months post-operatively. No systemic toxicity was detected; there were no serious adverse events, and ocular adverse events resolved. P1 and P2 showed statistically significant rod photoreceptor vision improvement by full-field stimulus testing in the treated eye. P1 also showed improvement in pupillary responses. Visual acuity remained stable from baseline in P1 and P2. P3, however, showed a gain of 0.3 logMAR in the treated eye, indicating greater cone-photoreceptor function. The results show safety and both rod- and cone-mediated efficacy of this therapy.

Transient pupillary light reflex in CEP290- or NPHP5-associated Leber congenital amaurosis: Latency as a potential outcome measure of cone function.

Mutations in photoreceptor cilium genes CEP290 and NPHP5 cause a form of Leber congenital amaurosis (LCA) which typically lacks rods but retains central cones. The current study evaluated the transient pupillary light reflex (TPLR) as an objective outcome measure to assess efficacy of ongoing and future therapies. Eleven eyes of six patients selected for retained cone function were tested with TPLR using full-field stimuli in the dark-adapted state. Stimuli were red or blue with 1 s duration and spanned a 6-log unit dynamic range. TPLR response amplitude was quantified at fixed times of 0.9 and 2 s after stimulus onset and TPLR latency was defined as the time to reach 0.3 mm constriction. Full-field stimulus testing (FST) and static perimetry were used to correlate subjective perception with objective TPLR parameters. TPLR and FST thresholds with both red and blue stimuli were abnormally elevated in patients to near -1.25 log phot-cd·m-2 consistent with the lack of rods. TPLR latencies were delayed on average but showed some differences among patients. Remnant extrafoveal vision was correlated with faster TPLR latencies. Our results support the use of a short TPLR protocol with full-field red stimuli of 0.7 log phot-cd·m-2 or brighter as an objective and convenient outcome measure of cone function in CEP290- and NPHP5-LCA. The latency parameter of the TPLR would be expected to show a detectable change when an intervention modifies cone sensitivity in the extrafoveal region.

Progress in treating inherited retinal diseases: Early subretinal gene therapy clinical trials and candidates for future initiatives.

Due to improved phenotyping and genetic characterization, the field of 'incurable' and 'blinding' inherited retinal diseases (IRDs) has moved substantially forward. Decades of ascertainment of IRD patient data from Philadelphia and Toronto centers illustrate the progress from Mendelian genetic types to molecular diagnoses. Molecular genetics have been used not only to clarify diagnoses and to direct counseling but also to enable the first clinical trials of gene-based treatment in these diseases. An overview of the recent reports of gene augmentation clinical trials by subretinal injections is used to reflect on the reasons why there has been limited success in this early venture into therapy. These first-in human experiences have taught that there is a need for advancing the techniques of delivery of the gene products - not only for refining further subretinal trials, but also for evaluating intravitreal delivery. Candidate IRDs for intravitreal gene delivery are then suggested to illustrate some of the disorders that may be amenable to improvement of remaining central vision with the least photoreceptor trauma. A more detailed understanding of the human IRDs to be considered for therapy and the calculated potential for efficacy should be among the routine prerequisites for initiating a clinical trial.

Treatment Potential for Macular Cone Vision in Leber Congenital Amaurosis Due to CEP290 or NPHP5 Mutations: Predictions From Artificial Intelligence.

Purpose: To use supervised machine learning to predict visual function from retinal structure in retinitis pigmentosa (RP) and apply these estimates to CEP290- and NPHP5-associated Leber congenital amaurosis (LCA) to determine the potential for functional improvement. Methods: Patients with RP (n = 20) and LCA due to CEP290 (n = 12) or NPHP5 (n = 6) mutations were studied. A patient with CEP290 mutations but mild retinal degeneration was included. RP patients had cone-mediated macular function. A machine learning technique was used to associate perimetric sensitivities to local structure in RP patients. Models trained on RP data were applied to predict visual function in LCA. Results: The RP and LCA patients had comparable retinal structure. RP patients had peak sensitivity at the fovea surrounded by decreasing sensitivity. Machine learning could successfully predict perimetry results from segmented or unsegmented optical coherence tomography (OCT) input. Application of machine learning predictions to LCA within the residual macular island of photoreceptor structure showed differences between predicted and measured sensitivities defining treatment potential. In patients with retained vision, the treatment potential was 4.6 ± 2.9 dB at the fovea but 16.4 ± 4.4 dB at the parafovea. In patients with limited or no vision, the treatment potential was 17.6 ± 9.4 dB. Conclusions: Cone vision improvement potential in LCA due to CEP290 or NPHP5 mutations is predictable from retinal structure using a machine learning approach. This should allow individual prediction of the maximal efficacy in clinical trials and guide decisions about dosing. Similar strategies can be used in other retinal degenerations to estimate the extent and location of treatment potential.

Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect.

Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. Ten patients with Leber congenital amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. NCT03140969 ) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3 months. The visual acuity of one exceptional responder improved from light perception to 20/400.