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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. Post hoc analyses and follow-up of a patient with Leber congenital amaurosis treated with the antisense oligonucleotide sepofarsen as part of a clinical trial indicates sustained improvement of vision 15 months after receiving a single dose of the drug., Author(s): Artur V. Cideciyan [sup.1] , Samuel G. Jacobson [sup.1] , Allen C. Ho [sup.2] , Alexandra V. Garafalo [sup.1] , Alejandro J. Roman [sup.1] , Alexander Sumaroka [sup.1] , [...]

L-cone opsin expression by gene therapy is a promising treatment for blue cone monochromacy (BCM) caused by congenital lack of long- and middle-wavelength-sensitive (L/M) cone function. Eight patients with BCM and confirmed pathogenic variants at the OPN1LW/OPN1MW gene cluster participated. Optical coherence tomography (OCT), chromatic perimetry, chromatic microperimetry, chromatic visual acuity (VA), and chromaticity thresholds were performed with unmodified commercial equipment and/or methods available in the public domain. Adaptive optics scanning laser ophthalmoscope (AOSLO) imaging was performed in a subset of patients. Outer retinal changes were detectable by OCT with an age-related effect on the foveal disease stage. Rod and short-wavelength-sensitive (S) cone functions were relatively retained by perimetry, although likely impacted by age-related increases in the pre-retinal absorption of short-wavelength lights. The central macula showed a large loss of red sensitivity on dark-adapted microperimetry. Chromatic VAs with high-contrast red gratings on a blue background were not detectable. Color vision was severely deficient. AOSLO imaging showed reduced total cone density with majority of the population being non-waveguiding. This study developed and evaluated specialized outcomes that will be needed for the determination of efficacy and safety in human clinical trials. Dark-adapted microperimetry with a red stimulus sampling the central macula would be a key endpoint to evaluate the light sensitivity improvements. VA changes specific to L-opsin can be measured with red gratings on a bright blue background and should also be considered as outcome measures in future interventional trials. [ABSTRACT FROM AUTHOR]

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. (https://clinicaltrials.gov/ct2/show/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. RNA antisense oligonucleotide therapy to restore normal splicing of a ciliopathy gene shows promising safety and efficacy results in a clinical trial to treat a form of childhood blindness., Author(s): Artur V. Cideciyan [sup.1] , Samuel G. Jacobson [sup.1] , Arlene V. Drack [sup.2] , Allen C. Ho [sup.3] , Jason Charng [sup.1] , Alexandra V. Garafalo [sup.1] , [...]

Mutations in the EYS (eyes shut homolog) gene are a common cause of autosomal recessive (ar) retinitis pigmentosa (RP). Without a mammalian model of human EYS disease, there is limited understanding of details of disease expression and rates of progression of the retinal degeneration. We studied clinically and with chromatic static perimetry, spectral-domain optical coherence tomography (OCT), and en face autofluoresence imaging, a cohort of 15 patients (ages 12-51 at first visit), some of whom had longitudinal data of function and structure. Rod sensitivity was able to be measured by chromatic perimetry in most patients at their earliest visits and some patients retained patchy rod function into the fifth decade of life. As expected from RP, cone sensitivity persisted after rod function was no longer measurable. The photoreceptor nuclear layer of the central retina was abnormal except at the fovea in most patients at first visit. Perifoveal disease measured over a period of years indicated that photoreceptor structural loss was followed by dysmorphology of the inner retina and loss of retinal pigment epithelial integrity. Although there could be variability in severity, preliminary analyses of the rates of vision loss suggested that EYS is a more rapidly progressive disease than other ciliopathies causing arRP, such as USH2A and MAK. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to determine the natural history of the photoreceptor disease in a large group of pediatric patients with RHD12-associated Leber congenital amaurosis (RDH12-LCA), to estimate the changes expected over the duration of a clinical trial, and to define the relationship between the photoreceptor loss and visual dysfunction., Methods: Forty-six patients representing 36 families were included. The great majority of patients were under the age of 18 years. Patients underwent complete ophthalmic examinations and imaging with various modalities including adaptive optics scanning laser ophthalmoscopy. Visual function was assessed with static and kinetic perimetry, and full-field stimulus test (FST) under dark- and light-adapted conditions., Results: Patients had a severe and early onset retinal degeneration (EORD). Visual acuity losses showed a progression rate of 0.04 logMAR per year. A small foveal island could be retained but showed degeneration over time. Foveal cone sensitivity losses were predictable by the loss of photoreceptors. Peripapillary retina could be retained with no significant progression detectable. Peripapillary rod sensitivity was substantially less than expected from photoreceptor structure pointing to a large improvement potential. FST sensitivities were reliably recordable in pediatric patients and showed a small but significant improvement with age. Locally and globally, loss of rod sensitivity tended to be larger than loss of cone sensitivity., Conclusions: Foveal cones of RDH12-LCA should be targeted with treatments aimed to slow progression, whereas peripapillary rod photoreceptors should be targeted with treatments aimed to improve night vision. Pediatric FST testing may be complicated by age-related maturation of decision making regarding threshold criteria.

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.

Purpose: To determine the progression rate and the variability of rod and cone sensitivities in patients with X-linked retinitis pigmentosa (XLRP) caused by mutations in ORF15-RPGR., Methods: ORF15-RPGR-XLRP patients (n = 15) were studied prospectively over 2 years with static perimetry sampling the visual field under dark-adapted and light-adapted conditions on a 12° square grid covering 168° width and 84° height. Natural history of rod and cone sensitivity loss and test-retest variability were estimated. Data were analyzed pointwise as well as averaged across small regions of neighboring loci of approximately 80 mm2 (900 deg2) in size representing the likely extent of localized gene therapy injections., Results: Retinal loci with mild to moderate loss of sensitivity tended to be in the mid- to far-peripheral retina in most patients. When averaged across small regions, dark-adapted rod vision progressed at an average of 2 dB per year with a coefficient of repeatability (CR) of 6.3 dB, and light-adapted cone vision with white stimulus progressed at an average of 0.9 dB per year with a CR of 3.8 dB. For an average patient enrolled in an early-phase clinical trial, significant (α = 0.05) progression would be predicted to occur with 80% power in 4.5 years for rod vision and 6.1 years for cone vision. Localization of regions in the temporal hemifield and grouping of results from multiple patients would permit trial designs of shorter duration., Conclusions: Measurement of rod sensitivity under dark-adapted conditions averaged across a small region showed the greatest potential for detectability of progression in the shortest period.

Purpose: To determine the progression of cone vision loss in patients with recessive disease from NR2E3 gene mutations., Methods: Patients with NR2E3 mutations (n = 37) were studied as a retrospective observational case series clinically and with chromatic static perimetry. Patients were investigated cross-sectionally, and a subset was followed longitudinally., Results: Patients showed a range of visual acuities; there was no clear relationship to age. With kinetic perimetry (V4e target), a full field could be retained over many years. Other patients showed progression from a full field, with or without pericentral scotomas, to a small central island. Three patterns of S-cone function were defined, based on percentage of hypersensitive S-cone loci in the field. From occupying most of the visual field, hyperfunctioning S-cone loci could diminish in percent, remaining largely in the periphery. Normal S-cone functioning then dominates, followed by the appearance of an annular region of abnormal S-cone loci approximately 10° to 40° from the fovea. Overall, S-cone sensitivity declined 2.6 times faster than L/M-cone sensitivity., Conclusions: Murine proof-of-concept studies suggest that clinical trials of patients with NR2E3 mutations may be forthcoming. Patterns of S-cone hyperfunction across the field would serve as a means to categorize patients as entry criteria or cohort selection in clinical trials. S-cone perimetry can be measured in the clinic and would be the logical efficacy monitor for therapeutic strategies. Given further understanding of the natural history of the disease, targeting the annular region of S-cone dysfunction for a focal therapy or for monitoring in a retina-wide intervention warrants consideration.