OBJECTIVE: To report a case of macular hole and detachment occurring after the subretinal injection of Voretigene Neparvovec (VN) in a patient affected by atypical RPE65 retinal dystrophy with high myopia and its successful surgical management.
METHODS: We report a case of a 70-year-old man treated with VN in both eyes. The best corrected visual acuity (BCVA) was 0.7 LogMar in the right eye (RE) and 0.92 LogMar in the left eye (LE). Axial length was 29.60 mm in the RE and 30.28 mm in the LE. Both eyes were pseudophakic. In both eyes, fundus examination revealed high myopia, posterior staphyloma, and extended retinal atrophy areas at the posterior pole, circumscribing a central island of surviving retina. Both eyes were treated with VN subretinal injection, but a full-thickness macular hole and retinal detachment occurred in the LE three weeks after surgery. The patient underwent 23-gauge vitrectomy with internal limiting membrane (ILM) peeling and the inverted flap technique with sulfur hexafluoride (SF6) 20% tamponade. Postoperative follow-up showed that the macular hole was closed and the BCVA was maintained.
CONCLUSIONS: Our experience suggests that patients with atypical RPE65 retinal dystrophy and high myopia undergoing VN subretinal injection require careful management to minimize the risk of macular hole and detachment occurrence and promptly detect and address these potential complications.

Genetic pediatric eye disease frequently leads to severe vision impairment or blindness. Voretigene neparvovec is the first approved gene therapy for an inherited retinal dystrophy (IRD). Voretigene neparvovec has been shown to be well tolerated and safe, with encouraging results in terms of efficacy, mainly when administered early in childhood. While we assisted at the first gene therapy available in clinical practice for an IRD, some questions remain unanswered, especially when gene therapy is delivered in young children. We review here the most recent reports and promising ongoing studies concerning various approaches on gene therapy in pediatric ophthalmology.

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.

Our study evaluated the morphological and functional outcomes, and the side effects, of voretigene neparvovec (VN) gene therapy for RPE65-mediated inherited retinal dystrophies (IRDs) in 12 eyes (six patients) at the Oxford Eye Hospital with a mean follow-up duration of 8.2 (range 1-12) months. All patients reported a subjective vision improvement 1 month after gene therapy. Best-corrected visual acuity (BCVA) remained stable (baseline: 1.28 (±0.71) vs. last follow-up: 1.46 (±0.60); p = 0.25). Average white Full-Field Stimulus Testing (FST) showed a trend towards improvement (baseline: -4.41 (±10.62) dB vs. last follow-up: -11.98 (±13.83) dB; p = 0.18). No changes in central retinal thickness or macular volume were observed. The side effects included mild intraocular inflammation (two eyes) and cataracts (four eyes). Retinal atrophy occurred in 10 eyes (eight mild, two severe) but did not impact FST measurements during the follow-up period. Increased intraocular pressure (IOP) was noted in three patients (six eyes); four eyes (two patients) required glaucoma surgery. The overall safety and effectiveness of VN treatment in our cohort align with previous VN clinical trials, except for the higher occurrence of retinal atrophy and increased IOP in our cohort. This suggests that raised IOP and retinal atrophy may be more common than previously reported.

Mutations in the RPE65 gene, associated with Leber congenital amaurosis, early-onset severe retinal dystrophy, and retinitis pigmentosa, gained growing attention since gene therapy for patients with RPE65-associated retinal dystrophy is available in clinical practice. RPE65 gene accounts for a very small proportion of patients with inherited retinal degeneration, especially Asian patients. Because RPE65-associated retinal dystrophy shares common clinical characteristics, such as early-onset severe nyctalopia, nystagmus, low vision, and progressive visual field constriction, with retinitis pigmentosa by other genetic mutations, appropriate genetic testing is essential to make a correct diagnosis. Also, fundus abnormalities can be minimal in early childhood, and the phenotype is highly variable depending on the type of mutations in RPE65-associated retinal dystrophy, which makes a diagnostic difficulty. The aim of this paper is to review the epidemiology of RPE65-associated retinal dystrophy, mutation spectrum, genetic diagnosis, clinical characteristics, and voretigene neparvovec, a gene therapy product for the treatment of RPE65-related retinal dystrophy.

UNASSIGNED: To evaluate the accuracy, quality, and readability of online information regarding the Food and Drug Administration (FDA) approved ocular gene therapy voretigene neparvovec (Luxturna, Spark Therapeutics, Philadelphia, PA, USA).
UNASSIGNED: Ten online resources about voretigene neparvovec were assessed in this cross-sectional study. A novel 25-question assessment was created to evaluate the information most relevant to patients. Each article was assessed by independent graders using the assessment and the DISCERN instrument. An online readability tool, Readable, was used to assess readability. Accountability was evaluated using the Journal of the American Medical Association (JAMA) benchmarks.
UNASSIGNED: The average questionnaire score for all the articles was 33.93 (SD 11.21, CI 95% ±6.95) out of 100 possible points with significant variation in the content accuracy and quality between the articles (P=0.017). EyeWiki achieved the highest score and MedicineNet the lowest. The mean reading grade for all articles was 12.88 (SD 1.93, CI 95% ±1.19) with significant variation between articles (P=0.001). Wikipedia was the most readable, and the FDA website was the least. None of the articles achieved all four JAMA benchmarks, and only one of the ten articles, EyeWiki, achieved three of the four JAMA benchmarks.
UNASSIGNED: The information available online regarding this FDA-approved ocular gene therapy is generally of low quality, above the average reading level of the general population, and varies significantly between sources. The articles provide incomplete information that is not entirely accurate or easy to read, and as a result, the material would not support patients adequately in their medical decisions and questions about this new therapeutic option.

Over 2 million people worldwide are suffering from gene-related retinal diseases, inherited or acquired, and over 270 genes have been identified which are found to be responsible for these conditions. This review article touches upon the mechanisms of gene therapy, various enzymes of the visual cycle responsible for different genetic diseases, Luxturna-the first US Food and Drug Administration (FDA)-approved therapeutic gene product, and several ongoing trials of gene therapy for age-related macular degeneration. Gene therapy has tremendous potential for retinal conditions due to its ease of accessibility, immune-privileged status, and tight blood-retinal barriers, limiting systemic side effects of the drug. In recent years, advances in gene therapy in retinal conditions have increasing significantly, with progress in cell-specific targeting and transduction efficiency of gene products through the use of adeno-associated viral vectors (AAVs), suggesting that even greater success in future clinical trials is possible.

OBJECTIVE: Leber congenital amaurosis type 2 (LCA2) and early-onset severe retinal dystrophy (EOSRD) are linked to visual impairment with nyctalopia and visual acuity reduction in early childhood. In 2017, the first gene therapy voretigene neparvovec (Luxturna™) for patients with LCA and EOSRD cause by bi-allelic mutations in the RPE65 gene has been approved. Here we report on an example of short-term change in the foveal morphology after functionally successful gene therapy with voretigene neparvovec in a 15-year old patient.
METHODS: The clinical examinations included best corrected visual acuity (BCVA), spectral domain optical coherence tomography (OCT) and adaptive optics retinal imaging.
RESULTS: During follow-up over a period of 3 months after the treatment, an improvement of the central foveal morphology could be observed in OCT, with a clear demarcation of the external limiting membrane and changes in the photoreceptor mosaic on adaptive optics retinal imaging. These morphological rescue parameters correlated in part with the improvement in foveal-mediated vision after the treatment and adaptive optics imaging. Although the visual acuity improved only slightly at month 3, objective central cone evaluation with chromatic pupil campimetry showed an increase in the central sensitivity. In daily life, the patient reported her visional experience after the treatment as \'brighter\'.
CONCLUSIONS: Rapid changes in the correlates of photoreceptor morphology after successful gene therapy in patients with LCA/EORD can be quantifiable on individual level.

This research aimed to establish recommendations on the clinical and genetic characteristics necessary to confirm patient eligibility for gene supplementation with voretigene neparvovec.
An expert steering committee comprising an interdisciplinary panel of Italian experts in the three fields of medical specialisation involved in the management of RPE65-associated inherited retinal disease (IRD) (medical retina, genetics, vitreoretinal surgery) proposed clinical questions necessary to determine the correct identification of patients with the disease, determine the fundamental clinical and genetics tests to reach the correct diagnosis and to evaluate the urgency to treat patients eligible to receive treatment with voretigene neparvovec. Supported by an extensive review of the literature, a series of statements were developed and refined to prepare precisely constructed questionnaires that were circulated among an external panel of experts comprising ophthalmologists (retina specialists, vitreoretinal surgeons) and geneticists with extensive experience in IRDs in Italy in a two-round Delphi process.
The categories addressed in the questionnaires included clinical manifestations of RPE65-related IRD, IRD screening and diagnosis, gene testing and genotyping, ocular gene therapy for IRDs, patient eligibility and prioritisation and surgical issues. Response rates by the survey participants were over 90% for the majority of items in both Delphi rounds. The steering committee developed the key consensus recommendations on each category that came from the two Delphi rounds into a simple and linear diagnostic algorithm designed to illustrate the patient pathway leading from the patient\'s referral centre to the retinal specialist centre.
Consensus guidelines were developed to guide paediatricians and general ophthalmologists to arrive at the correct diagnosis of RPE65-associated IRD and make informed clinical decisions regarding eligibility for a gene therapy approach to RPE65-associated IRD. The guidelines aim to ensure the best outcome for the patient, based on expert opinion, the published literature, and practical experience in the field of IRDs.

Voretigene neparvovec (VN) is the first gene therapy in ophthalmology for patients with RPE65-mediated hereditary retinal dystrophy. It has recently obtained European market approval, which is subject to strict regulatory and organizational conditions for its use. Here, we analyze the main studies supporting the authorization of this new therapy and describe the necessary steps to take at a hospital level for optimal administration to patients following current regulations.