Long-term Follow-up of a Phase 1/2a Clinical Trial of a Stem Cell-Derived Bioengineered Retinal Pigment Epithelium Implant for Geographic Atrophy.

PURPOSE: To report long-term results from a phase 1/2a clinical trial assessment of a scaffold-based human embryonic stem cell-derived retinal pigmented epithelium (RPE) implant in patients with advanced geographic atrophy (GA). DESIGN: A single-arm, open-label phase 1/2a clinical trial approved by the United States Food and Drug Administration. PARTICIPANTS: Patients were 69-85 years of age at the time of enrollment and were legally blind in the treated eye (best-corrected visual acuity [BCVA], ≤ 20/200) as a result of GA involving the fovea. METHODS: The clinical trial enrolled 16 patients, 15 of whom underwent implantation successfully. The implant was administered to the worse-seeing eye with the use of a custom subretinal insertion device. The companion nonimplanted eye served as the control. The primary endpoint was at 1 year; thereafter, patients were followed up at least yearly. MAIN OUTCOME MEASURES: Safety was the primary endpoint of the study. The occurrence and frequency of adverse events (AEs) were determined by scheduled eye examinations, including measurement of BCVA and intraocular pressure and multimodal imaging. Serum antibody titers were collected to monitor systemic humoral immune responses to the implanted cells. RESULTS: At a median follow-up of 3 years, fundus photography revealed no migration of the implant. No unanticipated, severe, implant-related AEs occurred, and the most common anticipated severe AE (severe retinal hemorrhage) was eliminated in the second cohort (9 patients) through improved intraoperative hemostasis. Nonsevere, transient retinal hemorrhages were noted either during or after surgery in all patients as anticipated for a subretinal surgical procedure. Throughout the median 3-year follow-up, results show that implanted eyes were more likely to improve by > 5 letters of BCVA and were less likely to worsen by > 5 letters compared with nonimplanted eyes. CONCLUSIONS: This report details the long-term follow-up of patients with GA to receive a scaffold-based stem cell-derived bioengineered RPE implant. Results show that the implant, at a median 3-year follow-up, is safe and well tolerated in patients with advanced dry age-related macular degeneration. The safety profile, along with the early indication of efficacy, warrants further clinical evaluation of this novel approach for the treatment of GA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Long-term observations of macular thickness after subretinal implantation of a photovoltaic prosthesis in patients with atrophic age-related macular degeneration.

Objective. Subretinal prostheses electrically stimulate the residual inner retinal neurons to partially restore vision. We investigated the changes in neurosensory macular structures and it is thickness associated with subretinal implantation in geographic atrophy (GA) secondary to age-related macular degeneration (AMD).Approach. Using optical coherence tomography, changes in distance between electrodes and retinal inner nuclear layer (INL) as well as alterations in thickness of retinal layers were measured over time above and near the subretinal chip implanted within the atrophic area. Retinal thickness (RT) was quantified across the implant surface and edges as well as outside the implant zone to compare with the natural macular changes following subretinal surgery, and the natural course of dry AMD.Main results. GA was defined based on complete retinal pigment epithelium and outer retinal atrophy (cRORA). Based on the analysis of three patients with subretinal implantation, we found that the distance between the implant and the target cells was stable over the long-term follow-up. Total RT above the implant decreased on average, by 39 ± 12µm during 3 months post-implantation, but no significant changes were observed after that, up to 36 months of the follow-up. RT also changed near the temporal entry point areas outside the implantation zone following the surgical trauma of retinal detachment. There was no change in the macula cRORA nasal to the implanted zone, where there was no surgical trauma or manipulation.Significance. The surgical delivery of the photovoltaic subretinal implant causes minor RT changes that settle after 3 months, and then remain stable over long-term with no adverse structural or functional effects. Distance between the implant and the INL remains stable up to 36 months of the follow-up.

Transplantation of Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium in a Swine Model of Geographic Atrophy.

BACKGROUND: The aim of this study was to test the feasibility and safety of subretinal transplantation of human induced pluripotent stem cell (hiPSC)-derived retinal pigment epithelium (RPE) cells into the healthy margins and within areas of degenerative retina in a swine model of geographic atrophy (GA). METHODS: Well-delimited selective outer retinal damage was induced by subretinal injection of NaIO3 into one eye in minipigs (n = 10). Thirty days later, a suspension of hiPSC-derived RPE cells expressing green fluorescent protein was injected into the subretinal space, into the healthy margins, and within areas of degenerative retina. In vivo follow-up was performed by multimodal imaging. Post-mortem retinas were analyzed by immunohistochemistry and histology. RESULTS: In vitro differentiated hiPSC-RPE cells showed a typical epithelial morphology, expressed RPE-related genes, and had phagocytic ability. Engrafted hiPSC-RPE cells were detected in 60% of the eyes, forming mature epithelium in healthy retina extending towards the border of the atrophy. Histological analysis revealed RPE interaction with host photoreceptors in the healthy retina. Engrafted cells in the atrophic zone were found in a patchy distribution but failed to form an epithelial-like layer. CONCLUSIONS: These results might support the use of hiPSC-RPE cells to treat atrophic GA by providing a housekeeping function to aid the overwhelmed remnant RPE, which might improve its survival and therefore slow down the progression of GA.

Effect of Human Central Nervous System Stem Cell Subretinal Transplantation on Progression of Geographic Atrophy Secondary to Nonneovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the effect of subretinally transplanted human central nervous system stem cells (HuCNS-SC) on the progression of geographic atrophy (GA) in patients with nonneovascular age-related macular degeneration (AMD). DESIGN: Multicenter, prospective, phase 1 open-label clinical trial. PARTICIPANTS: Fifteen patients with bilateral GA solely the result of AMD. METHODS: The eye with the worst best-corrected visual acuity from each patient was selected for treatment and was considered the study eye; fellow eyes served as controls. A total of 0.25 × 106 or 1.0 × 106 HuCNS-SCs were infused directly into the subretinal space, superotemporal to the fovea near the junctional zone, outside the area of GA. All patients underwent spectral-domain OCT and fundus autofluorescence imaging using the Spectralis HRA+OCT (Heidelberg Engineering, Inc., Heidelberg, Germany). Total GA area in both eyes was measured at baseline and month 12 by certified reading center graders using the Spectralis Region Finder software. Sectoral (clock hour) per directional radial GA progression rates with respect to the foveal center in both eyes were calculated using the polar transformation method in Image J software (National Institutes of Health, Bethesda, MD). To facilitate comparative analysis across the cohort, all eyes were transformed to a right-eye orientation. MAIN OUTCOME MEASURES: Total GA area and sectoral per directional GA progression rates were compared in both study and control eyes. RESULTS: No statistically significant difference was found in mean change in total GA area at month 12 between study and fellow eyes (1.07 ± 0.84 mm2 vs. 2.08 ± 1.97 mm2; P = 0.08). However, the month 12 sectoral per directional radial GA growth rate for the superotemporal region (i.e., the location of HuCNS-SC transplantation) showed a significantly slower progression rate in study eyes than in fellow eyes (0.29 ± 0.58 mm vs. 1.08 ± 0.65 mm; P = 0.007). The progression rate in the superotemporal quadrant of the study eye was significantly slower than in the other 3 quadrants combined (P = 0.04). CONCLUSIONS: In this small pilot study, HuCNS-SC transplantation seems to be associated with slower expansion of the GA lesion in the transplanted quadrant. Larger confirmatory studies are required. Sectoral or directional analysis of growth rates of GA may be a useful approach for assessing the efficacy of locally delivered therapies.

Surgical Method for Implantation of a Biosynthetic Retinal Pigment Epithelium Monolayer for Geographic Atrophy: Experience from a Phase 1/2a Study.

PURPOSE: To report the intraoperative methods and anatomic results for subretinal implantation of an investigational human embryonic stem cell-derived retinal pigment epithelium (RPE) monolayer seeded on a synthetic substrate (California Project to Cure Blindness Retinal Pigment Epithelium 1 [CPCB-RPE1]) in geographic atrophy (GA). DESIGN: Single-arm, open label, prospective, nonrandomized, Phase 1/2a study. PARTICIPANTS: Advanced non-neovascular age-related macular degeneration (NNAMD). METHODS: The worse-seeing eye (≤20/200) of each subject underwent subretinal implantation of a single 3.5×6.25 mm CPCB-RPE1 implant with a preplanned primary end point of safety and efficacy at 365 days. Commercially available 23-gauge vitrectomy equipment, custom surgical forceps, and operating microscope with or without intraoperative OCT (iOCT) were used. Exact Wilcoxon rank-sum tests and Spearman rank correlation coefficients were used to assess the association of the percentage of the GA area covered by the implant with patient and surgery characteristics. The partial Spearman correlation coefficient was calculated for the correlation between duration of surgery and baseline GA size after adjustment for surgeon experience. MAIN OUTCOME MEASURES: Intraoperative exploratory measures are reported, including area of GA covered by implant, subretinal position of implant, duration of surgery, and incidence of adverse events. Operative recordings and reports were used to determine exploratory outcome measures. RESULTS: Sixteen subjects were enrolled with a median age of 78 years (range, 69-85 years). Median duration of the surgery for all subjects was 160 minutes (range, 121-466 minutes). Intraoperative OCT was used to guide subretinal placement in 9 cases. Intraoperative OCT was potentially useful in identifying pathology not evident with standard intraoperative visualization. Median GA area at baseline was 13.8 mm2 (range, 6.0-46.4 mm2), and median GA area left uncovered by the implant was 1.7 mm2 (range, 0-20.4 mm2). On average, 86.9% of the baseline GA area was covered by the implant. In 5 subjects, >90% of the GA area was covered. Baseline GA size was inversely correlated with percentage of GA area covered by the implant (rs=-0.72; P = 0.002). No unanticipated serious adverse events related to the implant or surgery were reported. CONCLUSIONS: Surgical implantation of CPCB-RPE1 targeted to the area of GA in subjects with advanced NNAMD is feasible in an outpatient setting. Intraoperative OCT is not necessary but potentially useful in identifying subretinal pathology and confirming implant location.

Suprachoroidal Adipose Tissue-Derived Mesenchymal Stem Cell Implantation in Patients with Dry-Type Age-Related Macular Degeneration and Stargardt's Macular Dystrophy: 6-Month Follow-Up Results of a Phase 2 Study.

This prospective clinical case series aimed to investigate the safety and efficacy of suprachoroidal adipose tissue-derived mesenchymal stem cell (ADMSC) implantation in patients with dry-type age-related macular degeneration (AMD) and Stargardt's macular dystrophy (SMD). This study included four patients with advanced-stage dry-type AMD and four patients with SMD who underwent suprachoroidal implantation of ADMSCs. The best-corrected visual acuity (BCVA) in the study was 20/200. The worse eye of the patient was operated on. Patients were evaluated on the first day, first week, and first, third, and sixth months postoperatively. BCVA, anterior segment and fundus examination, color photography, fundus autofluorescence, optical coherence tomography, and visual field examination were carried out at each visit. Fundus fluorescein angiography and multifocal electroretinography (mf-ERG) recordings were performed at the end of the first, third, and sixth months and anytime if necessary during the follow-up. All eight patients completed the sixth month follow-up. None of them had any systemic or ocular complications. All of the eight patients experienced visual acuity improvement, visual field improvement, and improvement in mf-ERG recordings. Stem cell treatment with suprachoroidal implantation of ADMSCs seems to be safe and effective in the treatment of dry-type AMD and SMD.

EPIRETINAL MEMBRANE IN NONEXUDATIVE AGE-RELATED MACULAR DEGENERATION: Anatomical Features, Visual Outcomes and Prognostic Factors.

PURPOSE: To evaluate clinical characteristics, assess surgical outcomes, and determine prognostic factors after vitrectomy for epiretinal membrane (ERM) associated with nonexudative age-related macular degeneration (AMD). METHODS: This study comprised 171 consecutive patients with idiopathic ERM (n = 132) or nonexudative AMD-associated ERM (AMD-ERM, n = 39) undergoing vitrectomy. Preoperative morphologic characteristics on spectral-domain optical coherence tomography images and postoperative outcomes of the two groups were compared. Factors influencing postoperative best-corrected visual acuity in the AMD-ERM group were also analyzed. RESULTS: The AMD-ERM group was more likely to have an ERM with a smooth appearance (P = 0.009), a less severe vessel traction score (P = 0.002), a thinner central foveal thickness (P = 0.016), and more photoreceptor disruption than idiopathic ERM group. Mean central foveal thickness improved from 404.92 ± 82.08 and 369.87 ± 68.17 µm at baseline to 339.77 ± 39.27 and 331.72 ± 45.76 µm 1 year after surgery in eyes with idiopathic ERM and AMD-ERM, respectively (all P < 0.001). Mean logarithm of the minimum angle of resolution best-corrected visual acuity improved from 0.30 (20/40) ± 0.21 and 0.32 (20/42) ± 0.18 at baseline to 0.02 (20/21) ± 0.09 and 0.13 (20/27) ± 0.17 1 year after surgery in the idiopathic ERM and AMD-ERM groups, respectively (all P < 0.001). Baseline integrity of the ellipsoid zone line (P = 0.009) and preoperative best-corrected visual acuity (P = 0.024) were significantly correlated with visual outcome in the AMD-ERM group. CONCLUSION: Morphologic differences between AMD-ERM and idiopathic ERM were identified. Vitrectomy resulted in significant anatomical and visual improvements in eyes with AMD-ERM, but final visual outcome was worse in these eyes than in those with idiopathic ERM.

[Future methods of treatment in age related macular degeneration]. / Terapii de viitor în tratamentul degenerescentei maculare legate de vârsta.

In the present time the treatment of Age Related Macular Degeneration (ARMD) begins to develop. Many medical therapies are presently tested in the two types of ARMD, geographic atrophy and exudative ARMD. In atrophic ARMD, new drugs are aimed to spare photoreceptors and the retinal pigment epithelium, to prevent oxidative damage on the retina and to suppress the inflammation process. In exudative ARMD, new therapies are already in use and in progress, especially the anti-VEGF factors, and others try to improve visual prognosis in targeting other mechanism or cells involved in the angiogenesis process. This article reviews and summarizes the available data, presented in several scientific meetings, congresses or given directly by the companies involved.

αA crystallin may protect against geographic atrophy-meta-analysis of cataract vs. cataract surgery for geographic atrophy and experimental studies.

BACKGROUND: Cataract and geographic atrophy (GA, also called advanced "dry" age-related macular degeneration) are the two major causes of visual impairment in the developed world. The association between cataract surgery and the development of GA was controversial in previous studies. METHODS/PRINCIPAL FINDINGS: We performed a meta-analysis by pooling the current evidence in literature and found that cataract is associated with an increased risk of geographic atrophy with a summary odds ratio (OR) of 3.75 (95% CI: 95% CI: 1.84-7.62). However, cataract surgery is not associated with the risk of geographic atrophy (polled OR=3.23, 95% CI: 0.63-16.47). Further experiments were performed to analyze how the αA-crystallin, the major component of the lens, influences the development of GA in a mouse model. We found that theαA-crystallin mRNA and protein expression increased after oxidative stress induced by NaIO(3) in immunohistochemistry of retinal section and western blot of posterior eyecups. Both functional and histopathological evidence confirmed that GA is more severe in αA-crystallin knockout mice compared to wild-type mice. CONCLUSIONS: Therefore, αA-crystallin may protect against geographic atrophy. This study provides a better understanding of the relationship between cataract, cataract surgery, and GA.

Autologous translocation of choroid and retinal pigment epithelium in geographic atrophy: long-term functional and anatomical outcome.

PURPOSE: To evaluate the long-term outcome of autologous graft of retinal pigment epithelium (RPE) in patients with geographic atrophy. METHODS: Ten patients with progressive geographic atrophy underwent translocation of an autologous graft of RPE, Bruch membrane and choroid. The visual acuity (VA), reading performance, microperimetry, optical coherence tomography (OCT), fundus autofluorescence, fluorescein angiography and indocyanine green angiography were assessed. RESULTS: No recurrence of RPE atrophy was seen. All but one transplant were revascularised. Vascularisation persisted throughout the 3 years' follow-up. Spectral-domain OCT in some cases showed intact photoreceptors or intact outer nuclear and outer plexiform layer overlying the graft. In three cases, the grafts were positioned eccentrically; these patients did not benefit from surgery. The mean VA decreased from 20/80 (range: 20/800 to 20/40) at baseline to 20/200 (range: perception of hand movements to 20/32) at last follow-up. In two patients, VA were stable from 20/50 to 20/32 and 20/40 at the last follow-up, respectively. Postoperative complications included retinal detachment due to proliferative vitreoretinopathy, macular pucker, iritis, branch retinal vein occlusion and secondary ocular hypertension. CONCLUSIONS: Some patients benefit for at least 3 years from a functioning RPE-choroid graft. Functional outcome in most patients, however, was limited due to complications and unfavourable patient selection.