Purpose

To evaluate the long-term efficacy of ciliary neurotrophic factor delivered via an intraocular encapsulated cell implant for the treatment of retinitis pigmentosa.

Design

Long-term follow-up of a multicenter, sham-controlled study.

Methods

Thirty-six patients at 3 CNTF4 sites were randomly assigned to receive a high- or low-dose implant in 1 eye and sham surgery in the fellow eye. The primary endpoint (change in visual field sensitivity at 12 months) had been reported previously. Here we measure long-term visual acuity, visual field, and optical coherence tomography (OCT) outcomes in 24 patients either retaining or explanting the device at 24 months relative to sham-treated eyes.

Results

Eyes retaining the implant showed significantly greater visual field loss from baseline than either explanted eyes or sham eyes through 42 months. By 60 months and continuing through 96 months, visual field loss was comparable among sham-treated eyes, eyes retaining the implant, and explanted eyes, as was visual acuity and OCT macular volume.

Conclusions

Over the short term, ciliary neurotrophic factor released continuously from an intravitreal implant led to loss of total visual field sensitivity that was greater than the natural progression in the sham-treated eye. This additional loss of sensitivity related to the active implant was reversible when the implant was removed. Over the long term (60-96 months), there was no evidence of efficacy for visual acuity, visual field sensitivity, or OCT measures of retinal structure.

Purpose

Choroideremia is an incurable, X-linked, recessive retinal dystrophy caused by loss of function mutations in the CHM gene. It is estimated to affect approximately 1 in 50,000 male patients. It is characterized by progressive degeneration of the retinal pigment epithelium, choroid, and photoreceptors, resulting in visual impairment and blindness. There is an unmet need in choroideremia, because currently, there are no approved treatments available for patients with the disease.

Methods

We review the patient journey, societal impact, and emerging treatments for patients with choroideremia.

Results

Its relative rarity and similarities with other retinal diseases in early years mean that diagnosis of choroideremia can often be delayed. Furthermore, its impact on affected individuals, and wider society, is also likely underestimated. AAV2-mediated gene therapy is an investigational treatment that aims to replace the faulty CHM gene. Early-phase studies reported potentially important visual acuity gains and maintenance of vision in some patients, and a large Phase 3 program is now underway.

Conclusion

Choroideremia is a disease with a significant unmet need. Interventions that can treat progression of the disease and improve visual and functional outcomes have the potential to reduce health care costs and enhance patient quality of life.

Purpose

To measure visual fields using two-color dark-adapted chromatic perimetry in a subset of participants in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A), a study of USH2A-mediated syndromic (USH2) and autosomal recessive nonsyndromic retinitis pigmentosa, determine percentage retaining rod function, and explore relationships between dark-adapted visual fields (DAVF) and rod function from ERG and full-field stimulus thresholds (FST).

Methods

Full-field rod mean sensitivity, number of rod loci, maximum sensitivity, DAVF full-field hill of vision (DAVF VTOT), and 30° hill of vision (DAVF V30) were measured in one eye for DAVF ancillary study participants (n = 49). Loci where cyan relative to red sensitivity was more than 5 dB on dark-adapted chromatic perimetry were considered rod mediated. Correlation coefficients between the DAVF measures and standard clinical measures were estimated, as were kappa statistics (κ) for agreement between DAVF and other measures of rod function.

Results

Of 49 participants tested with DAVF, 38 (78%) had evidence of rod function, whereas 15 (31%) had measurable rod ERGs. DAVF maximum sensitivity was highly correlated with FST white thresholds (r = -0.80; P < .001). Although not statistically significant, the number of rod loci and DAVF VTOT were lower in eyes with longer disease duration by 0.82 (95% confidence interval, -1.76, 0.12) loci/year and 0.59 (95% confidence interval, -1.82, 0.64) dB-steradians/year, respectively.

Conclusions

Rod-mediated function on FST and DAVF is present in many patients with symptomatic USH2A-related retinal degeneration, including some without measurable rod ERGs. RUSH2A longitudinal data will determine how these measures change with disease progression and whether they are useful for longitudinal studies in inherited retinal degenerations.

Purpose

To report on cases of unilateral perimacular atrophy after treatment with voretigene neparvovec-rzyl, in the setting of previous contralateral eye treatment with a different viral vector.

Design

Single-center, retrospective chart review.

Methods

In this case series, four patients between the ages of six and 11 years old with RPE65-related retinopathy were treated unilaterally with rAAV2-CB-hRPE65 as part of a gene augmentation clinical trial (NCT00749957). Six to 10 years later the contralateral eyes were treated with the Food and Drug Administration-approved drug, voretigene neparvovec-rzyl. Best-corrected visual acuity (BCVA), fundus photos, ocular coherence tomography, two-color dark-adapted perimetry, full field stimulus threshold testing (FST), and location of subretinal bleb and chorioretinal atrophy were evaluated.

Results

Three out of four patients showed unilateral perimacular atrophy after treatment with voretigene, ranging from five to 22 months after treatment. Areas of robust visual field improvement were followed by areas of chorioretinal atrophy. Despite perimacular changes, BCVA, FST, and subjective improvements in vision and nyctalopia were maintained. Perimacular atrophy was not observed in the first eye treated with the previous viral vector.

Conclusions

We observed areas of robust visual field improvement followed by perimacular atrophy in voretigene treated eyes, as compared to the initially treated contralateral eyes.

Translational relevance

Caution is advised when using two different viral vectors between eyes in gene therapy. This may become an important issue in the future with increasing gene therapy clinical trials for inherited retinal dystrophies.

OBJECTIVE: To improve the understanding of the natural disease progression of retinitis pigmentosa GTPase regulator (RPGR)-associated X-linked retinitis pigmentosa (XLRP). DESIGN: A multicenter, prospective, observational natural history study over 24 months. PARTICIPANTS: Male participants aged ≥7 years with a pathogenic variant in the RPGR gene, a best-corrected visual acuity (BCVA) score of ≥34 ETDRS letters, and a mean 68-loci retinal sensitivity (assessed by microperimetry) of 0.1 to 20 decibels (dB). METHODS: Participants were divided into subgroups based on their BCVA score at baseline: 34 to 73 (lower BCVA) or ≥74 (higher BCVA) ETDRS letters. There were 7 visits over 24 months. MAIN OUTCOME MEASURES: Change from baseline in BCVA, retinal sensitivity, low luminance visual acuity (LLVA), fixation stability, contrast sensitivity, visual field, anatomical measures, 25-item Visual Function Questionnaire (VFQ-25), intraocular pressure, and adverse events (AEs). RESULTS: Overall, 201 participants were included. The mean (standard deviation [SD]) age was 30.3 (11.9) years in the lower BCVA subgroup (n = 170) and 27.7 (10.1) years in the higher BCVA subgroup (n = 31). The study eye baseline mean (SD) BCVA scores were 59.4 (10.30) and 77.3 (3.95) in the lower and higher BCVA subgroups, respectively; the lower BCVA subgroup had lower retinal sensitivity in the study eye at baseline than the higher BCVA subgroup. Over 24 months, there were small observed changes in BCVA, retinal sensitivity, LLVA, fixation, contrast sensitivity, and fundus photography findings. There were observed mean (SD) changes at 24 months in the lower and higher BCVA subgroups of -1.01 (4.67) and 0.03 (5.83) dB-steradians in the volume of full-field hill of vision, -330.6 (869.51) and -122.7 (22.01) μm in distance from foveal center to the nearest border of preserved fundus autofluorescence, -104.3 (277.80) and -207.1 (171.01) μm in central ellipsoid width, and -2.8 (9.7) and -0.6 (7.6) in VFQ-25 composite score, respectively. There was 1 death from completed suicide. There were no ocular serious adverse events, and most AEs were mild/moderate. CONCLUSIONS: This study provides evidence of the slow natural progression of XLRP over 24 months in both subgroups and provides important functional, anatomical, and safety data. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined were subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these four algorithms were included for further analysis. AnnotSV was used to annotate these SVs. SVs that overlap with known IRD-associated genes were examined with sequencing coverage, junction reads and discordant read pairs. Polymerase Chain Reaction (PCR) followed by Sanger sequencing was used to further confirm the SVs and identify the breakpoints. Segregation of the candidate pathogenic alleles with the disease was performed when possible. A total of 16 candidate pathogenic SVs were identified in 16 families, including deletions and inversions, representing 2.1% of patients with previously unsolved IRDs. Autosomal dominant, autosomal recessive and X-linked inheritance of disease-causing SVs were observed in 12 different genes. Among these, SVs in CLN3, EYS and PRPF31 were found in multiple families. Our study suggests that the contribution of SVs detected by short-read WGS is about 0.25% of our IRD patient cohort and is significantly lower than that of single nucleotide changes and small insertions and deletions.

The Foundation Fighting Blindness, a 501(c)(3) nonprofit organization, established an international consortium of inherited retinal disease specialists in 2016, with a mission to accelerate the development of treatments for rare, inherited retinal degenerations, such as retinitis pigmentosa, Stargardt disease, Leber congenital amaurosis, Usher syndrome, choroideremia, and achromatopsia. The Consortium accomplishes its mission by evaluating novel outcome measures, sharing standardized study protocols and datasets, and disseminating findings. Having established research infrastructure in the first 3 years, including 39 global research sites, the network is now poised to expand its infrastructure for trials of new therapies in partnership with industry. This model represents an innovative approach to overcome challenges of therapeutic development for rare diseases.

PURPOSE:To characterize a series of 7 patients with cone-rod dystrophy (CORD) and amelogenesis imperfecta (AI) owing to confirmed mutations in CNNM4, first described as "Jalili Syndrome." DESIGN:Retrospective observational case series. METHODS:Seven patients from 6 families with Jalili Syndrome were identified at 3 tertiary referral centers. We systematically reviewed their available medical records, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging (FAF), color fundus photography, and electrophysiological assessments. RESULTS:The mean age at presentation was 6.7 years (range 3-16 years), with 6 male and 1 female patient. CNNM4 mutations were identified in all patients. The mean Snellen best-corrected visual acuity (BCVA) at presentation was 20/246 (range 20/98 to 20/399) in the right eye and 20/252 (range 20/98 to 20/480) in the left. Nystagmus was observed in all 7 patients, and photophobia was present in 6. Funduscopic findings at presentation were variable, ranging from only mild disc pallor to retinal vascular attenuation and macular atrophy. Multimodal imaging demonstrated disease progression in all 7 patients over time. Electroretinography uniformly revealed progressive cone-rod dysfunction. CONCLUSIONS:Jalili Syndrome is a rare CORD associated with AI. We have further characterized its ocular phenotype, including describing SD-OCT, FAF, and electrophysiological features; and report several novel disease-causing sequence variants. Moreover, this study presents novel longitudinal data demonstrating structural and functional progression over time, allowing better informed advice on prognosis.

Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum. Here, we characterize the clinical phenotype of disease caused by variants in CEP78, CEP250, ARSG, and ABHD12.Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease-causing variants in CEP78, CEP250, ARSG, or ABHD12.CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL. ARSG variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. ABHD12-related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and non-congenital SNHL ranging from unreported to severe.This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted. Additionally, genetic screening may be useful in patients who have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH.

Purpose

To evaluate disease progression using static perimetry (SP) in patients with USH2A-related retinal degeneration, including Usher syndrome type 2 (USH2) and nonsyndromic autosomal recessive retinitis pigmentosa.

Design

Prospective, observational cohort study.

Methods

A total of 102 patients with biallelic disease-causing sequence variants in USH2A with baseline best-corrected visual acuity (BCVA) letter score ≥54 were recruited from 16 clinical sites in Europe and North America. SP, BCVA, full-field stimulus thresholds, spectral domain optical coherence tomography macular scans, and fundus-guided mesopic microperimetry were performed at baseline and annually. The main outcome measures were total hill of vision (V_TOT), hill of vision in the central 30° (V₃₀), V_TOT minus V₃₀ (V_PERIPH), and mean sensitivity.

Results

The average decline (95% CI) was 2.05 (1.40, 2.70) decibel-steradian (dB-sr)/y for V_TOT, 0.48 (0.32, 0.65) dB-sr/y for V₃₀, 1.53 (0.97, 2.08) dB-sr/y for V_PERIPH, and 0.55 (0.40, 0.71) dB/y for mean sensitivity. Average percentage decline per year was 8.3 (5.5, 11.1) for V_TOT, 5.2 (3.0, 7.4) for V₃₀, 16.0 (9.5, 22.0) for V_PERIPH, and 5.1 (3.5, 6.7) for mean sensitivity. Changes from baseline to year 2 in all SP measures were highly correlated (r's ranging from 0.52 [V₃₀ vs V_PERIPH] to 0.98 [V_TOT vs V_PERIPH]).

Conclusions

Quantitative measures of SP declined significantly over 2 years in USH2A-related retinal degeneration. The annual percentage rate of change was greatest for V_TOT and V_PERIPH, whereas V₃₀ and mean sensitivity changed least, reflecting earlier and more severe peripheral degeneration compared with central loss.