IMPORTANCE Intravitreal gene therapy is regarded as generally safe with limited mild adverse events, but its systemic effects remain to be investigated. OBJECTIVE To examine the association between immune response and intraocular inflammation after ocular gene therapy with recombinant adeno-associated virus 2 carrying the ND4 gene (rAAV2/2-ND4). DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of an open-label, dose-escalation phase 1/2 randomized clinical trial of rAAV2/2-ND4 included data from February 13, 2014 (first patient visit), to March 30, 2017 (last patient visit at week 96), the first 2 years after injection. Patients older than 15 years with diagnosed ND4 Leber hereditary optic neuropathy (LHON) and visual acuity of at least counting fingers were enrolled in 1 of 5 cohorts. Four dose cohorts of 3 patients each were treated sequentially. An extension cohort of 3 patients received the dose of 9 × 10 10 viral genomes per eye. INTERVENTIONS Patients received increasing doses of rAAV2/2-ND4 (9 × 10 9 , 3 × 10 10 , 9 × 10 10 , and 1.8 × 10 11 viral genomes per eye) as a single unilateral intravitreal injection. Patients were monitored for 96 weeks after injection; ocular examinations were performed regularly, and blood samples were collected for immunologic testing. MAIN OUTCOMES AND MEASURES A composite ocular inflammation score (OIS) was calculated based on grades of anterior chamber cells and flare, vitreous cells, and haze according to the Standardization of Uveitis Nomenclature. The systemic immune response was quantified by enzyme-linked immunospot (cellular immune response), enzyme-linked immunosorbent assay (IgG titers), and luciferase assay (neutralizing antibody [NAb] titers). RESULTS The present analysis included 15 patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) enrolled in the 5 cohorts of the clinical trial. Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration. Mild anterior chamber inflammation and vitritis were reported at all doses, and all cases were responsive to treatment. A maximum OIS of 9.5 was observed in a patient with history of idiopathic uveitis. Overall, OIS was not associated with the viral dose administered. No NAbs against AAV2 were detected in aqueous humor before treatment. Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment. Humoral immune response was not apparently associated with the dose administered or with the immune status of patients at baseline. No association was found between OISs and serum NAb titers. CONCLUSIONS AND RELEVANCE In this study, intravitreal administration of rAAV2/2-ND4 in patients with LHON was safe and well tolerated. Further investigations may shed light into the local immune response to rAAV2/2-ND4 as a potential explanation for the observed intraocular inflammation.

Background/objectives REALITY is an international observational retrospective registry of LHON patients evaluating the visual course and outcome in Leber hereditary optic neuropathy (LHON). Subjects/methods Demographics and visual function data were collected from medical charts of LHON patients with visual loss. The study was conducted in 11 study centres in the United States of America and Europe. The collection period extended from the presymptomatic stage to at least more than one year after onset of vision loss (chronic stage). A Locally Weighted Scatterplot Smoothing (LOWESS) local regression model was used to analyse the evolution of best-corrected visual acuity (BCVA) over time. Results 44 LHON patients were included; 27 (61%) carried the m.11778G>A ND4 mutation, 8 (18%) carried the m.3460G>A ND1 mutation, and 9 (20%) carried the m.14484T>C ND6 mutation. Fourteen (32%) patients were under 18 years old at onset of vision loss and 5 (11%) were below the age of 12. The average duration of follow-up was 32.5 months after onset of symptoms. At the last observed measure, mean BCVA was 1.46 LogMAR in ND4 patients, 1.52 LogMAR in ND1 patients, and 0.97 LogMAR in ND6 patients. The worst visual outcomes were reported in ND4 patients aged at least 15 years old at onset, with a mean BCVA of 1.55 LogMAR and no tendency for spontaneous recovery. The LOESS modelling curve depicted a severe and permanent deterioration of BCVA. Conclusions Amongst LHON patients with the three primary mtDNA mutations, adult patients with the m.11778G>A ND4 mutation had the worst visual outcomes, consistent with prior reports.

Background: Acute macular neuroretinopathy (AMN) is an increasingly diagnosed disorder associated with several diseases. The aim of this study was to report the incidence of AMN cases diagnosed during the 2020 coronavirus disease 2019 (COVID-19) pandemic year in a French hospital, and to describe their different forms. Methods: All patients diagnosed between 2019 and 2020, in Paris Rothschild Foundation Hospital, with AMN, paracentral acute middle maculopathy (PAMM) and multiple evanescent white dot syndrome (MEWDS) were retrospectively collected using the software Ophtalmoquery® (Corilus, V1.86.0018, 9050 Gand, Belgium). Systemic and ophthalmological data from AMN patients were analyzed. Results: Eleven patients were diagnosed with AMN in 2020 vs. only one patient reported in 2019. The incidence of AMN significantly increased from 0.66/100,000 visits in 2019 to 8.97/100,000 visits in 2020 (p = 0.001), whereas the incidence of PAMM and MEWDS remained unchanged. Four (36%) of these AMN patients were tested for COVID-19 and received positive polymerase chain reaction (PCR) tests. Conclusions: The incidence of AMN cases increased significantly in our institution in 2020, which was the year of the COVID-19 pandemic. All AMN-tested patients received a positive COVID PCR test, suggesting a possible causative link. According to the different clinical presentations, AMN may reflect different severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pathogenic mechanisms.

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