Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia.

Retinal gene therapy is increasingly recognized as a novel molecular intervention that has huge potential in treating common causes of blindness, the majority of which have a genetic aetiology1-5. Choroideremia is a chronic X-linked retinal degeneration that was first described in 18726. It leads to progressive blindness due to deficiency of Rab-escort protein 1 (REP1). We designed an adeno-associated viral vector to express REP1 and assessed it in a gene therapy clinical trial by subretinal injection in 14 patients with choroideremia. The primary endpoint was vision change in treated eyes 2 years after surgery compared to unoperated fellow eyes. Despite complications in two patients, visual acuity improved in the 14 treated eyes over controls (median 4.5 letter gain, versus 1.5 letter loss, P = 0.04), with 6 treated eyes gaining more than one line of vision (>5 letters). The results suggest that retinal gene therapy can sustain and improve visual acuity in a cohort of predominantly late-stage choroideremia patients in whom rapid visual acuity loss would ordinarily be predicted.

Optical coherence tomography imaging in the management of the Argus II retinal prosthesis system.

PURPOSE: To report a real-life experience with the Argus II retinal prosthesis system in blind patients with end-stage retinitis pigmentosa (RP) or choroideremia (CHM), focusing on the pivotal role of optical coherence tomography (OCT) in both preoperative and postoperative management. METHODS: This hospital-based case series included 3 blind patients who were uneventfully implanted with Argus II epiretinal device. These patients (2 with RP and 1 with CHM) were selected during the Argus™ II Retinal Prosthesis System PostMarket Surveillance Study Protocol. Complete screening procedures had involved 66 eyes of 33 patients afferent to the Center for Retinitis Pigmentosa of the Veneto Region. RESULTS: Preoperative OCT examination resulted in the exclusion of 8 eyes in 4 patients with bilateral posterior staphyloma diagnosing unexpected staphylomatous macular patterns in 2 patients with RP and no sign of pathologic myopia. Postoperative OCT study of Argus II proximity to retinal surface indicated a plausible correlation between electrode-retina distance and perceptual threshold in 2 of our 3 patients. In particular, during the first 6 months of follow-up, the patient with the closest contact between device and macula showed a continuous vision-related improvement in the performance of several real-life tasks. CONCLUSIONS: The present findings illustrate the modalities by which each different OCT examination is an essential tool to optimize safety and efficacy profiles during Argus II protocol. Optical coherence tomography will be crucial for future investigative approaches on patient selection criteria and next-generation implant design.

Outcomes following cataract surgery in choroideremia.

PurposeTo present a case series of cataract surgery outcomes in choroideremia eyes with an emphasis on the safety of this common operation in advanced stages of the disease.MethodsA single centre retrospective interventional case series comprising six patients with varying degrees of visual loss secondary to choroideremia underwent cataract surgery at a single tertiary eye hospital. Pre- and post-operative best-corrected Snellen visual acuity, spectral domain optical coherence tomography (SD-OCT), and slit lamp examination were performed together with fundus autofluorescence (FAF) and colour fundus photographs.The prevalence of intra- or post-operative complications, post-operative visual outcome, and change in central macular thickness were recorded.ResultsThe pre-operative best-corrected Snellen visual acuity in the operated eyes ranged from 6/12 (20/40) to PL. All but one patient had either an objective or a subjective improvement in visual acuity. There was no evidence of retinal phototoxicity or post-operative cystoid macular oedema (CMO). Three patients developed early capsular fibrosis.ConclusionsAlthough the residual functioning retina in choroideremia patients may be potentially vulnerable, this report finds no evidence of iatrogenic vision loss after uncomplicated cataract surgery. This suggests that cataract surgery may be performed safely in choroideremia patients, although a guarded prognosis for visual improvement should be emphasized in the informed consent.

Macular hole surgery in patients with end-stage choroideremia.

OBJECTIVE: To assess macular hole surgery in patients with end-stage choroideremia with regard to anatomic closure and visual outcome. DESIGN: Retrospective, interventional case series. PARTICIPANTS: Thirty adult male patients with a diagnosis of advanced choroideremia were reviewed and underwent spectral domain optical coherence tomography (OCT) as part of the screening process for a gene therapy clinical trial. From within that cohort, 3 were identified as having a full-thickness macular hole (FTMH). METHODS: A 23-gauge pars plana vitrectomy was performed with peeling of the inner limiting membrane and gas tamponade. Preoperative best-corrected visual acuity ranged from perception of light to 6/24. MAIN OUTCOME MEASURES: Prevalence of FTMH in advanced choroideremia, morphologic phenotype characteristics of FTMH in OCT, pre- and postoperative best-corrected visual acuity, and closure rate after surgery. RESULTS: The prevalence of FTMH in advanced choroideremia in our cohort was 10%. One hole was associated with significant macular schisis, presumed to be attributable to degeneration of outer retinal layers. Anatomic closure was achieved in all 3 patients and confirmed with spectral domain OCT. Gas tamponade lasted approximately twice as long as might be expected compared with standard FTMH surgery. Objective visual acuity did not improve; however, perceived vision improved in all patients. CONCLUSIONS: Although FTMH in choroideremia is a rare finding, it could potentially mask central progression of the disease. Regular screening may help to diagnose holes at an earlier stage when the visual prognosis after surgery may be better. Standard macular hole surgery seems to be effective in gaining anatomic closure, which would be significant for patients who subsequently require macula detachment for subretinal gene therapy. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

The Argus II epiretinal prosthesis system allows letter and word reading and long-term function in patients with profound vision loss.

BACKGROUND: Retinal prosthesis systems (RPS) are a novel treatment for profound vision loss in outer retinal dystrophies. Ideal prostheses would offer stable, long-term retinal stimulation and reproducible spatial resolution in a portable form appropriate for daily life. METHODS: We report a prospective, internally controlled, multicentre trial of the Argus II system. Twenty-eight subjects with light perception vision received a retinal implant. Controlled, closed-group, forced-choice letter identification, and, open-choice two-, three- and four-letter word identification tests were carried out. RESULTS: The mean±SD percentage correct letter identification for 21 subjects tested were: letters L, T, E, J, F, H, I, U, 72.3±24.6% system on and 17.7±12.9% system off; letters A, Z, Q, V, N, W, O, C, D, M, 55.0±27.4% system on and 11.8%±10.7% system off, and letters K, R, G, X, B, Y, S, P, 51.7±28.9% system on and 15.3±7.4% system off. (p<0.001 for all groups). A subgroup of six subjects was able to consistently read letters of reduced size, the smallest measuring 0.9 cm (1.7°) at 30 cm, and four subjects correctly identify unrehearsed two-, three- and four-letter words. Average implant duration was 19.9 months. CONCLUSIONS: Multiple blind subjects fitted with the Argus II system consistently identified letters and words using the device, indicating reproducible spatial resolution. This, in combination with stable, long-term function, represents significant progress in the evolution of artificial sight.

Fluorescein angiographic findings in eyes of patients with a subretinal electronic implant.

PURPOSE: One approach for restoring vision in end-stage hereditary retinal diseases is implantation of a subretinal microphotodiode array. We analyzed retinal fluorescein angiography findings of the implant area. METHODS: In this pilot study, patients (n = 11; 10 men, one woman; ages 45.2 ± 8.7 years), with visual acuity of light perception or worse resulting from a hereditary retinal degenerative disease, received active electronic subretinal visual implants. Implants were removed after 4 weeks (n = 7 subjects) or 4 months (n = 4 subjects). Following implantation, regular fluorescein angiography was performed. Regions of retinal capillary loss, microaneurysms, capillary alterations, neovascularization and leakage over the implant were scored at time points T1 (days 1-14), T2 (days 15-28) and T3 (months 3-4). Occurrence and changes of fluorescein angiographic phenomena are reported. RESULTS: In terms of the number of patients in whom retinal alterations were observed (compared to available images) the occurences of the angiographic phenomena (for time points T1, T2 and T3, respectively) were as follows: regions of capillary loss (five of seven, 10 of 11 and five of five patients), microaneurysms (0 of seven, two of 11 and three of five patients), calibre alterations of the capillaries (three of seven, eight of 11 and five of five patients), retinal neovascularization (one of seven, one of 11 and 0 of five) and leakage (three of seven, seven of 11 and four of five). The Friedman test revealed no significant changes in capillary loss, calibre alteration of the capillaries, neovascularization or leakage. Microaneurysms increased significantly (p = 0.037). CONCLUSIONS: Subretinal visual implants lead to increased capillary microaneurysms, a possible compensatory mechanism following recovery of inner retinal activity. There were no significant changes in capillary loss, calibre alteration of the capillaries, retinal neovascularization and leakage at 4 months. Further study will determine whether and to what degree long-term vascular changes are affected by the surgical procedure, the implant itself and/or recovery of retinal neuronal activity.