Gene therapy for Leber hereditary optic neuropathy.

INTRODUCTION: Leber hereditary optic neuropathy (LHON) is among the most frequent inherited mitochondrial disease, causing a severe visual impairment, mostly in young-adult males. The causative mtDNA variants (the three common are m.11778 G>A/MT-ND4, m.3460 G>A/MT-ND1, and m.14484T>C/MT-ND6) by affecting complex I impair oxidative phosphorylation in retinal ganglion cells, ultimately leading to irreversible cell death and consequent functional loss. The gene therapy based on allotopic expression of a wild-type transgene carried by adeno-associated viral vectors (AVV-based) appears a promising approach in mitochondrial disease and its efficacy has been explored in several large clinical trials. AREAS COVERED: The review work employed basic concepts in mitochondrial diseases, LHON, and gene therapy procedures. Reports from completed trials in LHON (i.e. RESCUE) were reviewed and critically compared. EXPERT OPINION: New challenges, as the improvement of the contralateral untreated eye or the apparently better outcome in patients treated in later stages (6-12 months), were highlighted by the latest gene therapy trials. A better understanding of the pathogenetic mechanisms of the disease together with combined therapy (medical and gene therapy) and optimization in genetic correction approaches could improve the visual outcome of treated eyes.

Rate and associations of inner retinal thinning in eyes with retinal vein occlusion and regressed macular oedema.

PURPOSE: To investigate the associations between visual acuity (VA) and structural optical coherence tomography (OCT) features in retinal vein occlusion (RVO) eyes after cystoid macular oedema (CMO) regression and to assess whether inner retinal thinning is progressive. METHODS: Retrospective observational study of RVO eyes with regressed CMO for at least 6 months. OCT scans at CMO regression were analysed, and features were correlated with VA at that visit. The inner retinal thickness was longitudinally compared between RVO and unaffected fellow eyes (controls) with linear mixed models. The rate of inner retinal thinning was obtained as the interaction term between disease status and time. Associations between inner retinal thinning and clinical characteristics were explored. RESULTS: Thirty-six RVO eyes were followed for 34.2 ± 21.1 months after CMO regression. The presence of ellipsoid zone disruption (regression estimate[standard error(SE)] = 0.16[0.04] LogMAR vs. intact, p < 0.001) and lower inner retinal thickness (regression estimate[SE] = -0.25[0.12] LogMAR for 100-µm increase, p = 0.01) were associated with worse VA. The inner retinal thickness decreased faster in RVO than controls (rate of retinal thinning -0.27 ± 0.09 µm/month vs. -0.08 ± 0.11 µm/month, p = 0.01). Macular ischaemia was associated with a faster rate of retinal thinning (interaction term macular ischaemia*follow-up time, p = 0.04). CONCLUSION: Inner retinal and photoreceptors' layers integrity are associated with better visual acuity once CMO resolves. RVO eyes undergo progressive inner retinal thinning after CMO regression, faster in eyes with macular ischaemia.

Macular Neovascularization Secondary to Subclinical Angioid Streaks in Age-Related Macular Degeneration: Treatment Response to Anti-VEGF at 2-Year Follow-up.

INTRODUCTION: To characterize the response to antivascular endothelial growth factor (VEGF) treatment of macular neovascularization (MNV) secondary to age-related macular degeneration (AMD) with subclinical angioid streaks (AS) during a 2-year follow-up. METHODS: Retrospective, longitudinal, case-control, and multicentric study. Among a cohort of neovascular AMD population, we selected patients with subclinical AS and treatment-naïve MNV treated with anti-VEGF for a 2-year follow-up. An age- and sex-matched control group with treatment-naïve MNV secondary to AMD without subclinical AS was selected. Demographics and differences in treatment response (i.e., number of injections needed, anatomical and functional outcomes) between the two groups were analyzed. RESULTS: Among 102 eyes of 102 patients with neovascular AMD, 34 eyes of 34 patients (82 ± 6 years old) were included in the subclinical AS group, whereas 68 eyes of 68 patients (81 ± 6 years old, p = 0.342) in the control group. All eyes with subclinical AS presented RPD compared to 56% of eyes without subclinical AS (p < 0.001). During the 2-year follow-up, eyes with subclinical AS needed more injections (10.6 ± 3.2 vs 8.3 ± 3.1 injections for eyes with and without subclinical AS, respectively, p < 0.001). Visual acuity (VA) decreased during the treatment (from 0.53 ± 0.37 at the baseline to 0.69 ± 0.45 LogMAR at 2-year follow-up, p = 0.044) in eyes with subclinical AS; no VA changes were observed in the control group (p = 0.798). RPE atrophy at the end of the 2-year follow-up affected 74% of cases with subclinical AS and 29% of cases of the control group (p < 0.001). CONCLUSIONS: MNVs secondary to AMD with subclinical AS are characterized by worse functional and anatomical outcomes after 2-year anti-VEGF treatment compared to MNV secondary to AMD without subclinical AS, supporting the different pathophysiological mechanisms involved in this recently described AMD phenotype.

A new phenotype or retinal involvement in Steinert Disease: a case report.

PURPOSE: To report a case illustrating the association of Steinert Disease (SD) with peripheral retinal non-perfusion areas and epiretinal membrane. METHODS: Case report. RESULTS: A 47-year-old Caucasian female diagnosed with SD was referred for blurred vision in her right eye (RE). She presented bilateral ptosis with deficit of elevator muscle.Dilated fundus examination revealed altered macular reflex, peripheral vascular alterations, and ghost vessels bilaterally. Structural spectral domain optical coherence tomography (SD-OCT) showed an epiretinal membrane with a partial alteration of the foveal profile in the RE. Optical coherence tomography angiography (OCTA) images revealed no evidence of neovascular membrane in the macular region. Fluoresceine angiography (FA) showed retinal peripheral non perfusion areas and leakage in the late phases of the examination. CONCLUSION: Any retinal alteration should be considered during the ophthalmological examination of patients suffering from type 1 myotonic dystrophy. OCT and fluoresceine angiography should be performed evaluating the SD patient that complains about visual impairment.

Understanding the propensity to undergo genetic testing in patients affected by inherited retinal diseases: a twelve-item questionnaire.

BACKGROUND: The diagnosis of inherited retinal diseases (IRDs) can only be confirmed through genetic testing. The aim of our study is to investigate the propensity of Italian patients affected by IRDs to undergo genetic testing. MATERIALS AND METHODS: One hundred and thirty-two patients diagnosed with IRDs referred to Italian Retina Onlus were enrolled from 1st January 2021 to 31th December 2021 in this cross-sectional study to answer to a twelve-item questionnaire. RESULTS: One hundred and four patients were aware of the possibility of taking a genetic test, and 94 of them did. Most of genetically tested patients (93.6%) had been informed about advantages and limitations of genetic investigations. The most common reason for undergoing genetic testing was to gather information for their relatives, while the most frequent reason for patients not taking the test was lack of someone who encourages them to do so. Most of genetically tested patients believed that the results could aid medical research in the search for a treatment for IRDs, while who did not undergo DNA testing often did not have a clear opinion on the topic. Almost all patients (98.9%) performed the test through the Italian National Health System. CONCLUSIONS: Our study investigated the tendency of Italian patients affected by IRDs to undergo genetic testing, highlighting the importance of educating both patients and healthcare professionals on this topic.

Subretinal Pseudocysts: A Comprehensive Analysis of this Novel OCT Finding.

INTRODUCTION: In current clinical practice, several optical coherence tomography (OCT) biomarkers have been proposed for the assessment of severity and prognosis of different retinal diseases. Subretinal pseudocysts are subretinal cystoid spaces with hyperreflective borders and only a few single cases have been reported thus far. The aim of the study was to characterize and investigate this novel OCT finding, exploring its clinical outcome. METHODS: Patients were evaluated retrospectively across different centers. The inclusion criterion was the presence of subretinal cystoid space on OCT scans, regardless of concurrent retinal diseases. Baseline examination was set as the first time the subretinal pseudocyst was identified by OCT. Medical and ophthalmological histories were collected at baseline. OCT and OCT-angiography were performed at baseline and at each follow-up examination. RESULTS: Twenty-eight eyes were included in the study and 31 subretinal pseudocysts were characterized. Out of 28 eyes, 16 were diagnosed with neovascular age-related macular degeneration (AMD), 7 with central serous chorioretinopathy, 4 with diabetic retinopathy, and 1 with angioid streaks. Subretinal and intraretinal fluid were present in 25 and 13 eyes, respectively. Mean distance of the subretinal pseudocyst from the fovea was 686 µm. The diameter of the pseudocyst was positively associated with the height of the subretinal fluid (r = 0.46; p = 0.018) and central macular thickness (r = 0.612; p = 0.001). At follow-up, subretinal pseudocysts disappeared in most of the reimaged eyes (16 out of 17). Of these, two patients presented retinal atrophy at baseline examination and eight patients (47%) developed retinal atrophy at follow-up. Conversely, seven eyes (41%) did not develop retinal atrophy. CONCLUSION: Subretinal pseudocysts are precarious OCT findings, usually disclosed in a context of subretinal fluid, and are probably transient alterations within the photoreceptor outer segments and retinal pigment epithelium (RPE) layer. Despite their nature, subretinal pseudocysts have been associated with photoreceptor loss and incomplete RPE definition.