Summary 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 Stargardt's 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 (Stargardt's 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 Stargardt's 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.
Proliferative vitreoretinopathy (PVR) is a blinding disorder that occurs in eyes with rhegmatogenous retinal detachment and in eyes that have recently undergone retinal detachment surgery. There are ...presently no treatment strategies to reduce the risk of developing PVR in eyes with retinal detachment, and surgical intervention is the only option for eyes with retinal detachment and established PVR. Given the poor visual outcome associated with the surgical treatment of PVR, considerable work has been done to identify pharmacologic agents that could antagonize the PVR process. Intensive efforts to identify molecular determinants of PVR implicate vitreal growth factors. A surprise that emerged in the course of testing the ‘growth factor hypothesis’ of PVR was the existence of a functional relationship amongst growth factors that engage platelet-derived growth factor (PDGF) receptor α (PDGFRα), a receptor tyrosine kinase that is key to pathogenesis of experimental PVR. Vascular endothelial cell growth factor A (VEGF), which is best known for its ability to activate VEGF receptors (VEGFRs) and induce permeability and/or angiogenesis, enables activation of PDGFRα by a wide spectrum of vitreal growth factors outside of the PDGF family (non-PDGFs) in a way that triggers signaling events that potently enhance the viability of cells displaced into vitreous. Targeting these growth factors or signaling events effectively neutralizes the bioactivity of PVR vitreous and prevents PVR in a number of preclinical models. In this review, we discuss recent conceptual advances in understanding the role of growth factors in PVR, and consider the tangible treatment strategies for clinical application.
Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents is a commonly used therapy for numerous retinal diseases. The most commonly used of these medications are ...bevacizumab, ranibizumab, aflibercept, and brolucizumab. However, intravitreal administration of these agents is also associated with several inflammatory and non-inflammatory adverse events. The three inflammatory adverse events are sterile intraocular inflammation, brolucizumab-associated retinal vasculitis, and post-injection endophthalmitis. This narrative review summarizes the current literature regarding these conditions, including their epidemiology, presentation, management, outcomes, and pathogenesis. The inflammatory adverse events also share a number of overlapping features, which can make them difficult to discern from one another in a clinical context. This review discusses certain distinguishing features of these conditions that may aid providers in discerning between them and establishing the correct diagnosis.
Purpose To explore the visual and anatomic outcomes of patients with refractory or recurrent neovascular age-related macular degeneration (AMD) who were converted from bevacizumab and/or ranibizumab ...to aflibercept. Design Two-center, retrospective chart review. Methods Treatment history, visual acuity (VA), and central macular thickness (CMT) on spectral-domain optical coherence tomography were collected. Patients were divided into “refractory” (persistent exudation despite monthly injections) or “recurrent” (exudation suppressed, but requiring frequent injections). Results One hundred and two eyes of 94 patients were included; 68 were refractory and 34 were recurrent. Eyes received a mean of 20.4 prior bevacizumab/ranibizumab injections and a mean of 3.8 aflibercept injections. Mean follow-up was 18 weeks. Mean VA was 20/50-1 before conversion, 20/50-2 after 1 aflibercept injection ( P = .723), and 20/50+2 after the final injection ( P = .253). Subgroup analysis of refractory and recurrent cases also showed stable VA. Of the refractory cases, mean CMT had improved after 1 injection ( P < .001) and the final injection ( P < .001). Intraretinal ( P < .001) and subretinal ( P < .001) fluid decreased after 1 injection, and the mean injection interval was extended from 5.2 to 6.2 weeks ( P = .003). Of the recurrent cases, mean CMT improved after 1 injection ( P < .001) and the final injection ( P < .001). Intraretinal ( P = .003) and subretinal ( P = .046) fluid decreased after 1 injection, and the mean injection interval was extended from 7.2 to 9.5 weeks ( P = .001). Conclusions Converting patients with chronic neovascular AMD to aflibercept results in stabilized vision and improved anatomic outcomes, while allowing injection intervals to be extended.
This study evaluated the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, CA) in blind subjects with severe outer retinal degeneration.
Single-arm, prospective, ...multicenter clinical trial.
Thirty subjects were enrolled in the United States and Europe between June 6, 2007, and August 11, 2009. All subjects were followed up for a minimum of 6 months and up to 2.7 years.
The electronic stimulator and antenna of the implant were sutured onto the sclera using an encircling silicone band. Next, a pars plana vitrectomy was performed, and the electrode array and cable were introduced into the eye via a pars plana sclerotomy. The microelectrode array then was tacked to the epiretinal surface.
The primary safety end points for the trial were the number, severity, and relation of adverse events. Principal performance end points were assessments of visual function as well as performance on orientation and mobility tasks.
Subjects performed statistically better with the system on versus off in the following tasks: object localization (96% of subjects), motion discrimination (57%), and discrimination of oriented gratings (23%). The best recorded visual acuity to date is 20/1260. Subjects' mean performance on orientation and mobility tasks was significantly better when the system was on versus off. Seventy percent of the patients did not have any serious adverse events (SAEs). The most common SAE reported was either conjunctival erosion or dehiscence over the extraocular implant and was treated successfully in all subjects except in one, who required explantation of the device without further complications.
The long-term safety results of Second Sight's retinal prosthesis system are acceptable, and most subjects with profound visual loss perform better on visual tasks with system than without it.
To assess the safety and tolerability of E10030 (Fovista; Ophthotech, New York, NY), a platelet-derived growth factor (PDGF) antagonist, when administered in combination with an anti-vascular ...endothelial growth factor (VEGF) agent, ranibizumab (Lucentis; Genentech, South San Francisco, CA) 0.5 mg, by intravitreal injection in participants with neovascular age-related macular degeneration (NVAMD).
Prospective phase 1 clinical trial.
A total of 23 participants diagnosed with NVAMD and aged 50 years or older were enrolled.
Part 1 included 15 participants. Three participants received a single intravitreal E10030 (0.03 mg) injection and were subsequently given intravitreal ranibizumab (0.5 mg) injections at weeks 2, 6, and 10. Twelve participants (3 per group) received E10030 (0.03, 0.3, 1.5, or 3.0 mg) in combination with ranibizumab (0.5 mg) at day 0, month 1, and month 2 in an ascending manner. In Part 2 (8 participants), E10030 (0.3, 1.5, or 3.0 mg) in combination with ranibizumab (0.5 mg) was injected at day 0, month 1, and month 2.
Safety at week 12 was the primary outcome and included assessment of vital signs, laboratory tests, and serial eye examinations. Other safety metrics included assessment through week 24 of Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity (VA) and biomarker changes evaluated by optical coherence tomography (OCT) and fluorescein angiography (FA).
All doses of intravitreal E10030 administered in combination with ranibizumab were well tolerated. No dose-limiting toxicities or relevant safety events were noted at any dose level during the study. Investigators did not report adverse events related to E10030 or ranibizumab. Mean VA change was a gain of 14 letters, and 59% of participants gained ≥15 letters from baseline at week 12. On FA at week 12, there was an 85.5% mean reduction from baseline in choroidal neovascularization (CNV) size. On OCT at the week 12 visit, there was a mean decrease in center point thickness and central subfield thickness of 38.9% and 33.7%, respectively.
Intravitreal E10030 administered at doses up to 3 mg in combination with ranibizumab was well tolerated without evidence of systemic or ocular toxicity in participants with NVAMD. The changes in both mean VA and imaging biomarkers suggest a favorable short-term safety profile for the combination therapy of E10030 and ranibizumab.
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.
The study is a multicenter, single-arm, prospective clinical trial.
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).
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.
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.
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.
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.
The internal limiting membrane represents the structural interface between the retina and the vitreous and has been postulated to serve several essential functions. Recently, internal limiting ...membrane peeling has been used in the treatment of a variety of retinal disorders. We review the history, techniques, rationale, and outcomes of internal limiting membrane peeling.
A review of the literature.
Internal limiting membrane peeling has been used to successfully treat a variety of retinal disorders including macular hole, epiretinal membrane, diabetic macular edema, retinal vein occlusion, and others.
Internal limiting membrane peeling may serve as an important component in the armamentarium of retinal surgery.
Retinal detachment after open globe injury Stryjewski, Tomasz P; Andreoli, Christopher M; Eliott, Dean
Ophthalmology (Rochester, Minn.),
01/2014, Letnik:
121, Številka:
1
Journal Article
Recenzirano
Odprti dostop
To characterize the development of retinal detachment (RD) after open globe trauma.
Case-control study.
A total of 892 patients comprising 893 open globe injuries (OGIs), of whom 255 were ultimately ...diagnosed with RD, with the remaining eyes serving as controls.
Retrospective chart review of patients with OGIs presenting to the Massachusetts Eye and Ear Infirmary between 1999 and 2011. Kaplan-Meier analysis was used to estimate the time to detachment, and multivariable logistic regression was used to define the clinical factors associated with RD after OGI.
Demographic and clinical characteristics at the time of presentation after OGI, date of RD diagnosis, and last date of follow-up.
Primary repair of the open globe was typically undertaken within hours of presentation. A total of 255 eyes were ultimately diagnosed with RD after open globe trauma, yielding an incidence of 29% (95% confidence interval, 26-32). For eyes that developed RD, 27% (69/255) detached within 24 hours of primary open globe repair, 47% (119/255) detached within 1 week, and 72% (183/255) detached within 1 month. Multivariable regression analysis revealed the presence of vitreous hemorrhage (odds ratio OR, 7.29; P < 0.001), higher zone of injury (OR, 2.51 per integer increase in zone number; OR, 1.00-6.30; P < 0.001), and poorer logarithm of the minimum angle of resolution (logMAR) visual acuity at the time of presentation after OGI (OR, 2.41 per integer increase in logMAR visual acuity; OR, 1.00-81.30; P < 0.001) to be associated with RD. A screening tool was created: the Retinal Detachment after Open Globe Injury score.
Retinal detachment is common after open globe trauma, although often not appearing until days to weeks after the initial traumatic event. Several clinical variables at the time of initial presentation can predict the future risk of detachment.
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