Dean Eliott

Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies

BACKGROUND Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients. METHODS In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardts macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50,000, 100,000, and 150,000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardts macular dystrophy) and NCT01344993 (age-related macular degeneration). FINDINGS There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardts macular dystrophy. INTERPRETATION The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. FUNDING Advanced Cell Technology.

Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: A 3-Year Multicenter, Randomized, Controlled Clinical Trial

PURPOSE We studied the 3-year efficacy and safety results of a 4-year study evaluating fluocinolone acetonide (FA) intravitreal implants in eyes with persistent or recurrent diabetic macular edema (DME). DESIGN Prospective, evaluator-masked, controlled, multicenter clinical trial. PARTICIPANTS We included 196 eyes with refractory DME. METHODS Patients were randomized 2:1 to receive 0.59-mg FA implant (n = 127) or standard of care (SOC additional laser or observation; n = 69). The implant was inserted through a pars plana incision. Visits were scheduled on day 2, weeks 1, 3, 6, 12, and 26, and thereafter every 13 weeks through 3 years postimplantation. MAIN OUTCOME MEASURES The primary efficacy outcome was ≥15-letter improvement in visual acuity (VA) at 6 months. Secondary outcomes included resolution of macular retinal thickening and Diabetic Retinopathy Severity Score (DRSS). Safety measures included incidence of adverse events (AEs). RESULTS Overall, VA improved ≥3 lines in 16.8% of implanted eyes at 6 months (P=0.0012; SOC, 1.4%); in 16.4% at 1 year (P=0.1191; SOC, 8.1%); in 31.8% at 2 years (P=0.0016; SOC, 9.3%); and in 31.1% at 3 years (P=0.1566; SOC, 20.0%). The number of implanted eyes with no evidence of retinal thickening at the center of the macula was higher than SOC eyes at 6 months (P<0.0001), 1 year (P<0.0001; 72% vs 22%), 2 years (P=0.016), and 3 years (P=0.861). A higher rate of improvement and lower rate of decline in DRSS occurred in the implanted group versus the SOC group at 6 months (P=0.0006), 1 year (P=0.0016), 2 years (P=0.012), and 3 years (P=0.0207). Intraocular pressure (IOP) ≥30 mmHg was recorded in 61.4% of implanted eyes (SOC, 5.8%) at any time and 33.8% required surgery for ocular hypertension by 4 years. Of implanted phakic eyes, 91% (SOC, 20%) had cataract extraction by 4 years. CONCLUSIONS The FA intravitreal implant met the primary and secondary outcomes, with significantly improved VA and DRSS and reduced DME. The most common AEs included cataract progression and elevated IOP. The 0.59-mg FA intravitreal implant may be an effective treatment for eyes with persistent or recurrent DME. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Central Serous Chorioretinopathy Associated with Inhaled or Intranasal Corticosteroids

OBJECTIVE The purpose of the study is to investigate the relationship between inhaled or intranasal adrenergic agonists and corticosteroids and the development of central serous chorioretinopathy (CSC). DESIGN The medical records of three patients with CSC who were found to use inhaled adrenergic agents or corticosteroids or both were identified prospectively. A survey of members of the Retina, Macula, and Vitreous societies and the National Registry of Drug-Induced Ocular Side Effects identified three additional cases. RESULTS Six patients with CSC were found to be chronic users of corticosteroid (four patients) or both beta adrenergic agonist and corticosteroid (two patients) metered dose inhalers or nasal sprays. In three cases, there was a close temporal correlation between the use of a corticosteroid nasal spray and the development of CSC. CONCLUSIONS These findings suggest that, in patients who are susceptible, the periocular or systemic absorption of inhaled corticosteroids may be sufficient to produce CSC in humans, supporting previous hypotheses regarding the pathogenesis of the disorder. Further studies are needed to confirm this association and to determine whether inhaled adrenergic agents also contribute to the development of this disorder. Patients in whom CSC develops while using corticosteroid inhalers or nasal sprays should be alerted to the possible relationship between CSC and these agents.

Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation

Aims To evaluate the effect of switching to bevacizumab or ranibizumab after developing tachyphylaxis during anti-vascular endothelial growth factor (VEGF) therapy for choroidal neovascularisation (CNV). Methods The authors reviewed the records of all patients who received both ranibizumab and bevacizumab for treatment of CNV to identify those who developed tachyphylaxis, defined as optical coherence tomography evidence of initial decreased exudation followed by lack of further reduction or an increase in exudation. Signs of exudation included subreitnal fluid (SRF), pigment epithelial detachment (PED) and/or cystoid macular oedema (CMO). Results 26 eyes were included. 10 were initially treated with bevacizumab and then changed to ranibizumab for persistent SRF, PED and/or CMO. Of these, seven had occult CNV and three had predominantly classic CNV. One eye in the occult CNV group did not respond after being switched to ranibizumab. Six eyes had a positive therapeutic response, after one injection in four eyes, and after two or three injections in one eye each. In the classic group, two responded to ranibizumab and one did not. Sixteen eyes were initially treated with ranibizumab before changing to bevacizumab. Of these, 15 had occult CNV and 1 was predominantly classic. Three of the 16 eyes failed to respond to bevacizumab; 6 improved after one injection and 5 after two injections. Conclusions Patients with CNV who develop tachyphylaxis to ranibizumab or bevacizumab may respond to another anti-VEGF drug. The majority of cases (81%) in this series demonstrated at least some response after switching therapies.

Long-Term Results from an Epiretinal Prosthesis to Restore Sight to the Blind

PURPOSE Retinitis pigmentosa (RP) is a group of inherited retinal degenerations leading to blindness due to photoreceptor loss. Retinitis pigmentosa is a rare disease, affecting only approximately 100 000 people in the United States. There is no cure and no approved medical therapy to slow or reverse RP. The purpose of this clinical trial was to evaluate the safety, reliability, and benefit of the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) in restoring some visual function to subjects completely blind from RP. We report clinical trial results at 1 and 3 years after implantation. DESIGN The study is a multicenter, single-arm, prospective clinical trial. PARTICIPANTS There were 30 subjects in 10 centers in the United States and Europe. Subjects served as their own controls, that is, implanted eye versus fellow eye, and system on versus system off (native residual vision). METHODS The Argus II System was implanted on and in a single eye (typically the worse-seeing eye) of blind subjects. Subjects wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. MAIN OUTCOME MEASURES The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. RESULTS A total of 29 of 30 subjects had functioning Argus II Systems implants 3 years after implantation. Eleven subjects experienced a total of 23 serious device- or surgery-related adverse events. All were treated with standard ophthalmic care. As a group, subjects performed significantly better with the system on than off on all visual function tests and functional vision assessments. CONCLUSIONS The 3-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind from RP. Earlier results from this trial were used to gain approval of the Argus II by the Food and Drug Administration and a CE mark in Europe. The Argus II System is the first and only retinal implant to have both approvals.

Postoperative use of bevacizumab as an antifibrotic agent in glaucoma filtration surgery in the rabbit.

PURPOSE To evaluate the efficacy of bevacizumab as an antifibrotic agent after trabeculectomy in rabbits. METHODS Forty-two rabbits underwent trabeculectomy and were randomly assigned to receive a postoperative course of seven subconjunctival injections of bevacizumab (1.25 mg, 25 mg/mL), 5-fluorouracil (5-FU; 5 mg, 50 mg/mL), or balanced salt solution (BSS; 0.1 mL, control). Bleb survival and characteristics were evaluated over a 30-day period. The animals were killed on postoperative day (PD)10, PD20, and PD30. Histology and immunohistochemistry of the surgical eyes was performed to evaluate and grade the amount of scarring and fibrosis in each group. RESULTS Bevacizumab significantly improved the outcome of filtration surgery in this model. Bevacizumab prolonged bleb survival compared with the 5-FU and control groups (16.0 +/- 1.3 days vs. 6.9 +/- 0.6 and 7.4 +/- 0.85 days, respectively; P < 0.001). Bevacizumab-treated eyes had significantly larger and higher blebs than the control and 5-FU-treated groups (P < 0.05). Histologic analysis revealed that eyes treated with bevacizumab had significantly less postoperative scarring at the microscopic level at PD10 and PD20 (P = 0.009). CONCLUSIONS Postoperative subconjunctival injection of bevacizumab is associated with improved trabeculectomy bleb survival in the rabbit model. Bevacizumab may be a useful agent for improving success and limiting scar tissue formation after trabeculectomy.

Retinal Thickness Analysis by Race, Gender, and Age Using Stratus OCT

PURPOSE To detect differences in retinal thickness among patients of different race, gender, and age using Stratus OCT. DESIGN Cross-sectional study. METHODS In a multicenter, university-based study, 126 patients with no history of ocular disease were enrolled (78 diabetics without retinopathy and 48 nondiabetics). Optical coherence tomography measurements were performed using Stratus OCT. Statistical comparisons of center point foveal thickness and mean foveal thickness were made using generalized estimating equations adjusting for diabetic status, race, age, and gender. RESULTS The study population consisted of 36% male subjects, 39% Caucasian, 33% African-American, and 28% Hispanic. Mean foveal thickness was 191.6 +/- 2.7 microm and 194.5 +/- 2.7 microm for diabetics and nondiabetics, respectively (P = .49). Mean foveal thickness in male subjects was significantly larger than in female (201.8 +/- 2.7 microm and 186.9 +/- 2.6 microm, respectively; P < .001). Mean foveal thickness was 200.2 +/- 2.7 microm for Caucasian, 181.0 +/- 3.7 microm for African-American, and 194.7 +/- 3.9 microm for Hispanic subjects. Mean foveal thickness was significantly less for African-American than Caucasian (P < .0001) or Hispanic subjects (P = .005). Center point foveal thickness and mean foveal thickness showed a significant increase with age. CONCLUSIONS There are statistically significant differences in retinal thickness between subjects of different race, gender, and age. When compared to Caucasian and Hispanic subjects, African-American race is a predictor of decreased mean foveal thickness; and male sex (regardless of race) is a significant predictor of increased mean foveal thickness. Mean foveal thickness is similar among diabetics and nondiabetics when data are controlled for age, race, and sex. These results suggest that studies comparing OCT measurements should carefully control for age-based, race-based, and gender-based variations in retinal thickness.

Preliminary 6 month results from the argus tm ii epiretinal prosthesis feasibility study

The Argus™ II 60 channel epiretinal prosthesis has been developed in order to provide partial restoration of vision to subjects blinded from outer retinal degenerative disease. To date the device has been implanted in 21 subjects as part of a feasibility study. In 6 month post-implantation door finding and line tracking orientation and mobility testing, subjects have shown improvements of 86% and 73%, respectively, for system on vs. system off. In high-contrast Square Localization tests using a touch screen monitor 87% of tested subjects performed significantly better with the system on compared with off. These preliminary results show that the Argus II system provides some functional vision to blind subjects.

Acute macular neuroretinopathy: long-term insights revealed by multimodal imaging.

Purpose: To report the structural and functional changes in acute macular neuroretinopathy (AMN) and their long-term evolution. Multimodal retinal imaging was acquired, including Fourier domain optical coherence tomography (OCT), infrared (IR) reflectance, and near IR autofluorescence (NIA). Methods: In this retrospective observational case series, detailed clinical history and multimodal imaging are reported in eight patients with AMN. Manual segmentation of the Fourier domain OCT volume scans was done in one patient with the largest AMN lesion to yield retinal sublayer topographic maps. Results: Two patients were seen within the first 1 to 2 days of symptoms, and both showed outer nuclear and outer plexiform layer hyperreflectivity. Both patients developed enlargement of the lesion over the first week on IR reflectance imaging with a corresponding lateral extension of the outer retinal disruption on Fourier domain OCT. Thinning of the outer nuclear layer persisted in all patients with lesions >100 &mgr;m width, and in one patient this thinning worsened over the course of follow-up, as noted on the sublayer maps. This structural abnormality correlated with long-term functional deficits, persisting up to 14 months after the initial episode. Infrared reflectance highlights the lesion best, and abnormalities on near IR autofluorescence may be present. Conclusion: Acute macular neuroretinopathy acutely affects the outer nuclear and plexiform layers manifesting as OCT hyperreflectivity. The hallmark long-term changes are outer nuclear thinning on Fourier domain OCT and a fading dark lesion on IR reflectance imaging. These changes correspond to focal disruption of the outer segment/retinal pigment epithelium junction on OCT, and not the inner segment/outer segment junction, as previously reported. Optical coherence tomography and near IR autofluorescence abnormalities suggest previously unrecognized melanin and retinal pigment epithelium derangements in this condition.

Visual Prognosis in Autosomal Dominant Optic Atrophy (Kjer Type)

We examined 25 patients from three pedigrees with dominant optic atrophy (Kjer type). Follow-up on 20 patients ranged from five to 40 years (mean, 16 years; median, 13 years). Visual acuity ranged from 20/20 (in one 58-year-old man with an affected father and three affected children) to 20/400. The median initial visual acuity was 20/60, and the median final visual acuity was 20/80. Visual acuity remained unchanged or decreased by one Snellen line in both eyes of 13 patients (65%); it decreased between two and four Snellen lines in only one eye in three patients (15%) and in both eyes in four patients (20%). The rate of visual loss was unrelated to initial visual acuity or the particular pedigree to which the patient belonged. There was functional and ophthalmoscopic heterogeneity between and within the pedigrees. Eight patients perceived moderate to severe social or occupational handicap. Visual prognosis is relatively good in Kjers dominant optic atrophy with stable or slow progression of visual loss.