To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).
RESCUE is a multicenter, randomized, ...double-masked, sham-controlled, phase 3 clinical trial.
Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included.
Each subject’s right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye.
The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4–treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96.
Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4–treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4–treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from −0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4–treated and sham-treated eyes was −0.01 logMAR (P = 0.89); the primary end point of a −0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4–treated and sham-treated eyes, respectively.
At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.
A deep-learning system that was applied to 14,341 fundus photographs differentiated optic disks with papilledema from normal disks with 96.4% sensitivity and 84.7% specificity in an external-testing ...data set. The prevalence of papilledema was 9.5%, yielding positive and negative predictive values of 39.8% and 99.6%, respectively.
Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease that specifically targets the retinal ganglion cells by reducing their ability to produce enough energy to ...sustain. The mutations of the mitochondrial DNA that cause LHON are silent until an unknown trigger causes bilateral central visual scotoma. After the onset of loss of vision, most patients experience progressive worsening within the following months. Few of them regain some vision after a period of ~1 year. Management of LHON patients has been focused on understanding the triggers of the disease and its pathophysiology to prevent the onset of visual loss in a carrier. Medical treatment is recommended once visual loss has started in at least one eye. Research evaluated drugs that are thought to be able to restore the mitochondrial electron transport chain of the retinal ganglion cells. Significant advances were made in evaluating free radical cell scavengers and gene therapy as potential treatments for LHON. Although encouraging the results of clinical trial have been mixed in stopping the worsening of visual loss. In patients with chronic disease of over 1 year, efficient treatment that restores vision is yet to be discovered. In this review, we summarize the management strategies for patients with LHON before, during, and after the loss of vision, explain the rationale and effectiveness of previous and current treatments, and report findings about emerging treatments.
Background and objective
The prognosis in myelin oligodendrocyte glycoprotein (MOG) antibody‐associated disease (MOGAD) is a matter of debate. Our aim was to assess the long‐term outcomes of patients ...with MOGAD.
Methods
We retrospectively analysed the clinical and paraclinical data of patients from the French nationwide observatory study NOMADMUS who tested positive for MOG antibodies (MOG‐IgG) and who had clinical follow‐up of at least 8 years from their first episode.
Results
Sixty‐one patients (median range age at onset 27 3–69 years), with a median (mean; range) follow‐up of 177 (212.8; 98–657) months, were included. Among 58 patients with a relapsing course, 26.3% relapsed in the first year after onset. Of the 61 patients, 90.2% experienced at least one episode of optic neuritis. At last visit, the median (mean; range) Expanded Disability Status Scale (EDSS) score was 1 (2.12; 0–7.5), 12.5% had an EDSS score ≥6 and 37.5% had an EDSS score ≥3. Of 51 patients with final visual acuity (VA) data available, 15.7% had VA ≤0.1 in at least one eye and 25.5% had VA ≤0.5 in at least one eye. Bilateral blindness (VA ≤0.1) was present in 5.9% of patients. Finally, 12.5% of patients presented bladder dysfunction requiring long‐term urinary catheterization. No factor associated significantly with a final EDSS score ≥3 or with final VA ≤0.1 was found.
Conclusion
Overall long‐term favourable outcomes were achieved in a majority of our patients, but severe impairment, in particular visual damage, was not uncommon.
Sixty one patients with myelin oligodendrocyte glycoprotein antibody‐associated disease were included, of whom 90.2% experienced at least one episode of optic neuritis. At last visit (median range follow‐up of 177 98–657 months), the median (mean; range) Expanded Disability Status Scale (EDSS) score was 1 (2.12; 0–7.5), 12.5% had an EDSS score ≥6 and 15.7% had visual acuity (VA) ≤0.1. Bilateral blindness (VA ≤0.1) was present in 5.9% of patients. No factor was associated significantly with a final EDSS ≥3 or with final VA ≤0.1. Overall long‐term favourable outcomes were achieved in a majority of patients, but severe impairment, in particular visual damage, was not uncommon.
Background
The kappa free light chains index (κ‐index) is increasing in importance as a fast, easy, cost‐effective, and quantitative biomarker in multiple sclerosis (MS), which can replace ...cerebrospinal fluid (CSF)‐restricted oligoclonal bands (OCB) detection. In previous studies, controls often included mixed patients with several inflammatory central nervous system disorders. The aim of the present study was to assess the κ‐index in patients with serum aquaporin‐4 (AQP4)‐IgG or myelin‐oligodendrocyte‐glycoprotein (MOG)‐IgG.
Methods
We analyzed CSF/serum samples of patients with AQP4‐IgG or MOG‐Ig and evaluated distinct κ‐index cut‐offs. We described clinical and magnetic resonance imaging (MRI) features of patients with the highest κ‐index values.
Results
In 11 patients with AQP4‐IgG, median κ‐index was 16.8 (range 0.2; 63) and 6/11 (54.5%) had κ‐index >12. Among 42 patients with MOG‐IgG, 2 had low positive MOG‐IgG titers, were ultimately diagnosed with MS, and had a markedly increased κ‐index (54.1 and 102.5 respectively). For the remaining 40 MOG‐IgG‐positive patients the median κ‐index was 0.3 (range 0.1; 15.5). Some 6/40 (15%) and 1/40 (2.5%) patients had a κ‐index >6 and >12, respectively. None fulfilled MRI dissemination in space and dissemination in time (DIS/DIT) criteria and the final diagnosis was MOG‐IgG‐associated disease (MOGAD) for these 40 patients. Four of the 40 (10%) MOG‐IgG‐positive patients had OCB.
Conclusion
While a marked increase in κ‐index could discriminate MS from MOGAD, a low κ‐index threshold could lead to confusion between MS and MOGAD or AQP4 antibody‐positive neuromyelitis optica spectrum disorder.
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 × 1010 viral genomes per eye. INTERVENTIONS: Patients received increasing doses of rAAV2/2-ND4 (9 × 109, 3 × 1010, 9 × 1010, and 1.8 × 1011 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.
REALITY is an international observational retrospective registry of LHON patients evaluating the visual course and outcome in Leber hereditary optic neuropathy (LHON).
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.
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.
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.
Abstract
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.
Newman et al. report that bilateral injection of lenadogene nolparvovec improves vision in patients carrying the m.11778G>A MT-ND4 mutation causing Leber hereditary optic neuropathy, with a larger treatment effect in patients who received bilateral treatment and an excellent safety profile.
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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