Report From the Second Global Scientific Conference on Clinical Trial Design and Outcome Measures for RDH12-Associated Inherited Retinal Degeneration.

Translational Relevance: A multi-stakeholder, patient centric approach will be critical to the design of future successful clinical trials with outcome measures relevant to the RDH12-IRD population.

DIAGNOSTIC YIELD OF AN INHERITED RETINAL DISEASE GENE PANEL IN RETINOPATHY OF UNKNOWN ORIGIN.

PURPOSE: Evaluating the presence of class 3, 4, and 5 genetic variants in inherited retinal disease (IRD) genes in patients with retinopathy of unknown origin (RUO). METHODS: Multicentric retrospective study of RUO cases diagnosed between January 2012 and February 2022. General and ophthalmologic history, complete ophthalmologic examination, antiretinal antibodies, and IRD gene panel results were analyzed in every patient. Four RUO categories were defined: nonparaneoplastic autoimmune retinopathy, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy. RESULTS: The authors included 12 patients (9 females) across these four RUO categories. Mean age at inclusion was 45.6 years (20-68 years). Seven patients demonstrated class 3 variants in IRD genes. Of these, two also demonstrated class 5 variants in other IRD genes. The remaining five patients had negative panel results. IRD gene panel analysis allowed diagnosis refinement in 1 (8.3%) nonparaneoplastic autoimmune retinopathy patient in the RUO cohort. When considering the nonparaneoplastic autoimmune retinopathy subpopulation only, a higher diagnostic yield of 20% (1/5 patients) was achieved. CONCLUSION: Every suspected nonparaneoplastic autoimmune retinopathy patient should benefit from gene panel testing to not overlook undiagnosed IRDs. By contrast, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy subpopulations did not benefit from genetic testing in this study.

Genetic Testing of Patients with Inherited Retinal Diseases in the European Countries: An International Survey by the European Vision Institute.

INTRODUCTION: The purpose of this project was to explore the current standards of clinical care genetic testing and counseling for patients with inherited retinal diseases (IRDs) from the perspective of leading experts in selected European countries. Also, to gather opinions on current bottlenecks and future solutions to improve patient care. METHODS: On the initiative of the European Vision Institute, a survey questionnaire with 41 questions was designed and sent to experts in the field from ten European countries. Each participant was asked to answer with reference to the situation in their own country. RESULTS: Sixteen questionnaires were collected by November 2023. IRD genetic tests are performed in clinical care settings for 80% or more of tested patients in 9 countries, and the costs of genetic tests in clinical care are covered by the public health service to the extent of 90% or more in 8 countries. The median proportion of patients who are genetically tested, the median rate of genetically solved patients among those who are tested, and the median proportion of patients receiving counseling are 51-70%, 61-80%, and 61-80%, respectively. Improving the education of healthcare professionals who facilitate patient referrals to specialized centers, improving access of patients to more thorough genotyping, and increasing the number of available counselors were the most advocated solutions. CONCLUSION: There is a significant proportion of IRD patients who are not genetically tested, whose genetic testing is inconclusive, or who do not receive counseling. Educational programs, greater availability of state-of-the-art genotyping and genetic counselors could improve healthcare for IRD patients.

Characterising the refractive error in paediatric patients with congenital stationary night blindness: a multicentre study.

BACKGROUND/AAIMS: Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F, NYX and TRPM1. High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression. METHODS: This multicentre, retrospective study explored CSNB caused by variants in CACNA1F, NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated. RESULTS: 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F, NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F, NYX and TRPM1, respectively. CONCLUSIONS: Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia.

Bardet-Biedl syndrome improved diagnosis criteria and management: Inter European Reference Networks consensus statement and recommendations.

Four European Reference Networks (ERN-EYE, ERKNet, Endo-ERN, ERN-ITHACA) have teamed up to establish a consensus statement and recommendations for Bardet-Biedl syndrome (BBS). BBS is an autosomal recessive ciliopathy with at least 26 genes identified to date. The clinical manifestations are pleiotropic, can be observed in utero and will progress with age. Genetic testing has progressively improved in the last years prompting for a revision of the diagnostic criteria taking into account clinical Primary and Secondary features, as well as positive or negative molecular diagnosis. This consensus statement also emphasizes on initial diagnosis, monitoring and lifelong follow-up, and symptomatic care that can be provided to patients and family members according to the involved care professionals. For paediatricians, developmental anomalies can be at the forefront for diagnosis (such as polydactyly) but can require specific care, such as for associated neuro developmental disorders. For ophthalmology, the early onset retinal degeneration requires ad hoc functional and imaging technologies and specific care for severe visual impairment. For endocrinology, among other manifestations, early onset obesity and its complications has benefited from better evaluation of eating behaviour problems, improved lifestyle programs, and from novel pharmacological therapies. Kidney and urinary track involvements warrants lifespan attention, as chronic kidney failure can occur and early management might improve outcome. This consensus recommends revised diagnostic criteria for BBS that will ensure certainty of diagnosis, giving robust grounds for genetic counselling as well as in the perspective of future trials for innovative therapies.

Quality of life, functioning and participation of children and adolescents with visual impairment: A scoping review.

BACKGROUND: Vision has a key role in children's neuromotor, cognitive and social development. Children with visual impairment attain developmental milestones at later stages and are at higher risk of developing psychological disorders and social withdrawn. AIMS: We performed a scoping review to summarize the mostly used instruments assessing the impact of visual impairment on quality of life, functioning and participation of children and adolescents. In addition, the main findings of the included studies are discussed. METHODS AND PROCEDURES: We searched for papers assessing quality of life, functioning and participation of children and adolescents with visual impairment from 0 to 18 years old conducted between 2000 and 2023. OUTCOMES AND RESULTS: In total, 69 studies met the inclusion criteria and were included in the review. Child self-report, caregivers-proxy and self-report questionnaires as well as interviews were used. The results showed that quality of life, functioning and participation are significantly reduced in children and adolescents with visual impairment, and that the impact depends on different factors (e.g., severity of the impairment, age). CONCLUSIONS AND IMPLICATIONS: Considering the significant impact of visual impairment on quality of life, functioning and participation on this population, it is fundamental to develop integrated and multi-dimensional assessment programs that evaluate the impact of visual impairment on those dimensions considering different contexts of life (e.g., family, school, leisure time). WHAT THIS PAPER ADDS?: The present review aims to give an overview of what is known about the impact of visual impairment on quality of life, functioning and participation of children and adolescents. We assumed a biopsychosocial perspective which, in line with the definition of health by the International Classification of Functioning, Disability and Health (WHO, 2001), considered how body functions and structures, functioning, participation and environmental factors dynamically interact to define the health, or the disease, status of a person at a certain moment of life. We reported the most used instruments for the assessment of quality of life, participation, and functioning, with a specific interest on Patient-Reported Outcome Measures and self-report measures. By reporting the different instruments used, we gave a broad overview about the available tools that can be used in clinical as well as in research field to assess quality of life, functioning and participation in this population. Additionally, the review of the existing literature allowed us to demonstrate that those dimensions are negatively impacted by visual impairment and thus they should be considered in the assessment programs. Specifically, there is the need to provide more integrated assessment programs that investigate the impact of visual impairment on children and adolescents' social and emotional wellbeing, everyday functioning and social relationship, considering their subjective experience together with the one of caregivers, teachers, health care professionals, and other relevant adults involved in their life. Additionally, it is essential to plan and implement multidimensional assessment programs that consider how all areas of life are differently impacted by visual impairment.

A cohort study of 19 patients with gyrate atrophy of the choroid and retina (GACR).

PURPOSE: Gyrate atrophy of the choroid and retina (GACR) is an autosomal recessive inherited metabolic disorder (IMD) characterised by progressive retinal degeneration, leading to severe visual impairment. The rapid developments in ophthalmic genetic therapies warrant knowledge on clinical phenotype of eligible diseases such as GACR to define future therapeutic parameters in clinical trials. METHODS: Retrospective chart analysis was performed in nineteen patients. Data were analysed using IBM SPSS Statistics version 28.0.1.1. RESULTS: Nineteen patients were included with a mean age of 32.6 years (range 8-58). Mean age at onset of ophthalmic symptoms was 7.9 years (range 3-16). Median logMAR of visual acuity at inclusion was 0.26 (range -0.18-3.00). Mean age at cataract surgery was 28.8 years (n = 11 patients). Mean spherical equivalent of the refractive error was -8.96 (range -20.87 to -2.25). Cystoid maculopathy was present in 68% of patients, with a loss of integrity of the foveal ellipsoid zone (EZ) in 24/38 eyes. Of the 14 patients treated with dietary protein restriction, the four patients who started the diet before age 10 showed most benefit. CONCLUSION: This study demonstrates the severe ophthalmic disease course associated with GACR, as well as possible benefit of early dietary treatment. In addition to visual loss, patients experience severe myopia, early-onset cataract, and CME. There is a loss of foveal EZ integrity at a young age, emphasising the need for early diagnosis enabling current and future therapeutic interventions.

Anterior scleral thickness in Marfan syndrome: A quantitative analysis.

PURPOSE: To investigate the anterior scleral thickness (AST) in patients with Marfan syndrome (MFS). METHODS: A prospective, cross-sectional study was conducted at the Department of Ophthalmology, Ghent University Hospital, Ghent, including patients with a genetically confirmed clinical diagnosis of MFS and age-, gender- and axial length-matched controls. Subjects with known corneal, conjunctival or scleral pathology and a history of ocular surgery, including pars plana vitrectomy, recent contact lens use or high-grade astigmatism were excluded. Subjects underwent non-cycloplegic autorefraction, Scheimpflug-based corneal tomography, axial length measurement and spectral-domain optical coherence tomography (OCT). AST was manually measured at 1 mm (AST1), 2 mm (AST2) and 3 mm (AST3) from the scleral spur, temporally and nasally. RESULTS: A total of 56 subjects (28 subjects in the MFS group and 28 matched subjects in the control group) were included in this study. In patients with MFS, AST was significantly reduced compared to matched controls, both overall and at every analysed measuring point in the nasal and temporal areas (p < 0.001). Central corneal thickness (CCT) and mean keratometry (Kmean) values were significantly lower in patients with MFS (p < 0.05). A positive correlation was found between nasal AST and CCT in patients with MFS. No correlation was found between AST and Kmean or between AST and axial length. In patients with MFS with ectopia lentis, compared to those without, temporal AST3 was significantly lower (p < 0.05). AST was significantly lower in patients with MFS harbouring a variant predicted to cause haploinsufficiency compared to those with a variant expected to lead to a dominant negative effect for both nasal and temporal measurements. CONCLUSION: Based on anterior segment OCT measurements, AST of patients with MFS is significantly lower compared to matched controls.

Real-World Safety and Effectiveness of Voretigene Neparvovec: Results up to 2 Years from the Prospective, Registry-Based PERCEIVE Study.

Voretigene neparvovec (VN) is the first available gene therapy for patients with biallelic RPE65-mediated inherited retinal dystrophy who have sufficient viable retinal cells. PERCEIVE is an ongoing, post-authorization, prospective, multicenter, registry-based observational study and is the largest study assessing the real-world, long-term safety and effectiveness of VN. Here, we present the outcomes of 103 patients treated with VN according to local prescribing information. The mean (SD) age was 19.5 (10.85) years, 52 (50.5%) were female, and the mean (SD) duration of the follow up was 0.8 (0.64) years (maximum: 2.3 years). Thirty-five patients (34%) experienced ocular treatment-emergent adverse events (TEAEs), most frequently related to chorioretinal atrophy (n = 13 [12.6%]). Eighteen patients (17.5%; 24 eyes [13.1%]) experienced ocular TEAEs of special interest, including intraocular inflammation and/or infection related to the procedure (n = 7). The mean (SD) changes from baseline in full-field light-sensitivity threshold testing (white light) at month 1, month 6, year 1, and year 2 were -16.59 (13.48) dB (51 eyes), -18.24 (14.62) dB (42 eyes), -15.84 (14.10) dB (10 eyes), and -13.67 (22.62) dB (13 eyes), respectively. The change in visual acuity from baseline was not clinically significant. Overall, the outcomes of the PERCEIVE study are consistent with the findings of VN pivotal clinical trials.

Mutations in SAMD7 cause autosomal-recessive macular dystrophy with or without cone dysfunction.

Sterile alpha motif domain containing 7 (SAMD7) is a component of the Polycomb repressive complex 1, which inhibits transcription of many genes, including those activated by the transcription factor Cone-Rod Homeobox (CRX). Here we report bi-allelic mutations in SAMD7 as a cause of autosomal-recessive macular dystrophy with or without cone dysfunction. Four of these mutations affect splicing, while another mutation is a missense variant that alters the repressive effect of SAMD7 on CRX-dependent promoter activity, as shown by in vitro assays. Immunostaining of human retinal sections revealed that SAMD7 is localized in the nuclei of both rods and cones, as well as in those of cells belonging to the inner nuclear layer. These results place SAMD7 as a gene crucial for human retinal function and demonstrate a significant difference in the role of SAMD7 between the human and the mouse retina.

Combining a prioritization strategy and functional studies nominates 5'UTR variants underlying inherited retinal disease.

BACKGROUND: 5' untranslated regions (5'UTRs) are essential modulators of protein translation. Predicting the impact of 5'UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach of a comprehensive prioritization strategy and functional assays to evaluate 5'UTR variation in two large cohorts of patients with inherited retinal diseases (IRDs). METHODS: We performed an isoform-level re-analysis of retinal RNA-seq data to identify the protein-coding transcripts of 378 IRD genes with highest expression in retina. We evaluated the coverage of their 5'UTRs by different whole exome sequencing (WES) kits. The selected 5'UTRs were analyzed in whole genome sequencing (WGS) and WES data from IRD sub-cohorts from the 100,000 Genomes Project (n = 2397 WGS) and an in-house database (n = 1682 WES), respectively. Identified variants were annotated for 5'UTR-relevant features and classified into seven categories based on their predicted functional consequence. We developed a variant prioritization strategy by integrating population frequency, specific criteria for each category, and family and phenotypic data. A selection of candidate variants underwent functional validation using diverse approaches. RESULTS: Isoform-level re-quantification of retinal gene expression revealed 76 IRD genes with a non-canonical retina-enriched isoform, of which 20 display a fully distinct 5'UTR compared to that of their canonical isoform. Depending on the probe design, 3-20% of IRD genes have 5'UTRs fully captured by WES. After analyzing these regions in both cohorts, we prioritized 11 (likely) pathogenic variants in 10 genes (ARL3, MERTK, NDP, NMNAT1, NPHP4, PAX6, PRPF31, PRPF4, RDH12, RD3), of which 7 were novel. Functional analyses further supported the pathogenicity of three variants. Mis-splicing was demonstrated for the PRPF31:c.-9+1G>T variant. The MERTK:c.-125G>A variant, overlapping a transcriptional start site, was shown to significantly reduce both luciferase mRNA levels and activity. The RDH12:c.-123C>T variant was found in cis with the hypomorphic RDH12:c.701G>A (p.Arg234His) variant in 11 patients. This 5'UTR variant, predicted to introduce an upstream open reading frame, was shown to result in reduced RDH12 protein but unaltered mRNA levels. CONCLUSIONS: This study demonstrates the importance of 5'UTR variants implicated in IRDs and provides a systematic approach for 5'UTR annotation and validation that is applicable to other inherited diseases.

Efficacy of Carbonic Anhydrase Inhibitors on Cystoid Fluid Collections and Visual Acuity in Patients with X-Linked Retinoschisis.

PURPOSE: To date, there is no standard treatment regimen for carbonic anhydrase inhibitors (CAIs) in X-linked retinoschisis (XLRS) patients. This retrospective study aims to evaluate the efficacy of CAIs on visual acuity and cystoid fluid collections (CFC) in XRLS patients in Dutch and Belgian tertiary referral centers. DESIGN: Retrospective cohort study. PARTICIPANTS: Forty-two patients with XLRS. METHODS: In total, 42 patients were enrolled. To be included, patients had to have previous treatment with an oral CAI (acetazolamide), a topical CAI (brinzolamide/dorzolamide), or a combination of an oral and a topical CAI for at least 4 consecutive weeks. We evaluated the effect of the CAI on best-corrected visual acuity (BCVA) and central foveal thickness (CFT) on OCT. MAIN OUTCOME MEASURES: Central foveal thickness and BCVA. RESULTS: The median age at the baseline visit of the patients in this cohort study was 14.7 (range, 43.6) years, with a median (interquartile range [IQR]) follow-up period of 4.0 (2.2-5.2) years. During the follow-up period, 25 patients were treated once with an oral CAI (60%), 24 patients were treated once with a topical CAI (57%), and 11 patients were treated once with a combination of both topical and oral CAI (26%). We observed a significant reduction of CFT for oral CAI by 14.37 µm per 100 mg per day (P < 0.001; 95% confidence interval [CI], -19.62 to -9.10 µm) and for topical CAI by 7.52 µm per drop per day (P = 0.017; 95% CI, -13.67 to -1.32 µm). The visual acuity changed significantly while on treatment with oral CAI by -0.0059 logMAR per 100 mg (P = 0.008; 95% CI, -0.010 to -0.0013 logMAR). Seven patients (17%) had side effects leading to treatment discontinuation. CONCLUSIONS: Our data indicate that treatment with (oral) CAI may be beneficial for short-term management of CFC in patients with XLRS. Despite a significant reduction in CFT, the change in visual acuity was modest and not of clinical significance. Nonetheless, the anatomic improvement of the central retina in these patients may be of value to create an optimal retinal condition for future potential treatment options such as gene therapy. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Paediatric cataract surgery with 27G vitrectomy instrumentation: the Ghent University Hospital Experience.

Objective: To describe a cohort of paediatric patients who underwent unilateral or bilateral lens extractions at Ghent University hospital using the Dutch Ophthalmic Research Center (D.O.R.C.) ultra-short 27G vitrectomy system. Methods: Retrospective analysis of the medical and surgical records of all children that underwent lens extraction between September 2016 and September 2020 using the D.O.R.C. ultra-short 27G vitrectomy system. Results: Seventy-two eyes of 52 patients were included. The most important aetiologies in this study were of secondary (25.5%), developmental (13.7%), or genetic (13.7%) nature. No definitive cause could be established in more than a quarter of cases (27.5%) despite extensive work-up, them being deemed idiopathic. The remainder of cases (19.6%) was not assigned a final aetiologic designation at the time of the study due to contradicting or missing diagnostic data. This study could not identify any cataract cases related to infection or trauma. Surgical complications rate was 61.1% of which posterior capsule opacification was the most frequent with a rate of 25%. A significant short-term postoperative best-corrected visual acuity gain (≤ -0.2 LogMAR) was observed in 60.5% of eyes for which usable acuity data were available (n = 38). Conclusion: Many different instruments and techniques have been described and used in the context of paediatric lens extractions, each with its advantages and disadvantages. This study illustrates that an ultra-short 27G vitrectomy system can be used to perform paediatric lens extractions with good surgical outcomes. Further studies and comparative trials are needed to ascertain this further.

Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis.

Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.

Therapeutic landscape for inherited ocular diseases: Current and emerging therapies.

Inherited ocular diseases comprise a heterogeneous group of rare and complex diseases, including inherited retinal diseases (IRDs) and inherited optic neuropathies. Recent success in adeno-associated virus-based gene therapy, voretigene neparvovec (Luxturna®) for RPE65-related IRDs, has heralded rapid evolution in gene therapy platform technologies and strategies, from gene augmentation to RNA editing, as well as gene agnostic approaches such as optogenetics. This review discusses the fundamentals underlying the mode of inheritance, natural history studies and clinical trial outcomes, as well as current and emerging therapies covering gene therapy strategies, cell-based therapies and bionic vision.

Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy.

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.

Outcome of Cataract Surgery in Patients With Retinitis Pigmentosa.

PURPOSE: To assess the visual outcome of cataract surgery in patients with retinitis pigmentosa (RP). DESIGN: Retrospective, noncomparative clinical study. METHODS: Preoperative, intraoperative, and postoperative data of patients with RP who were undergoing cataract surgery were collected from several expertise centers across Europe. RESULTS: In total, 295 eyes of 226 patients were included in the study. The mean age at surgery of the first eye was 56.1 ± 17.9 years. Following surgery, best-corrected visual acuity (BCVA) improved significantly from 1.03 to 0.81 logMAR (ie, 20/214 to 20/129 Snellen) in the first treated eye (-0.22 logMAR; 95% CI = -0.31 to -0.13; P < .001) and from 0.80 to 0.56 logMAR (ie, 20/126 to 20/73 Snellen) in the second treated eye (-0.24 logMAR; 95% CI = -0.32 to -0.15; P < .001). Marked BCVA improvements (postoperative change in BCVA of ≥0.3 logMAR) were observed in 87 of 226 patients (39%). Greater odds for marked visual improvements were observed in patients with moderate visual impairment or worse. The most common complications were zonular dialysis (n = 15; 5%) and (exacerbation of) cystoid macular edema (n = 14; 5%), respectively. Postoperative posterior capsular opacifications were present in 111 of 295 eyes (38%). CONCLUSION: Significant improvements in BCVA are observed in most patients with RP following cataract surgery. Baseline BCVA is a predictor of visual outcome. Preoperative evaluation should include the assessment of potential zonular insufficiency and the presence of CME, as they are relatively common and may increase the risk of complications.

Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation.

INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P < 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 44.4%; P < 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was - 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P < 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection. CONCLUSION: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection. TRIAL REGISTRATION NUMBERS: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).