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.

One-Year Follow-Up in a Phase 1/2a Clinical Trial of an Allogeneic RPE Cell Bioengineered Implant for Advanced Dry Age-Related Macular Degeneration.

Purpose: To report 1-year follow-up of a phase 1/2a clinical trial testing a composite subretinal implant having polarized human embryonic stem cell (hESC)-derived retinal pigment epithelium (RPE) cells on an ultrathin parylene substrate in subjects with advanced non-neovascular age-related macular degeneration (NNAMD). Methods: The phase 1/2a clinical trial included 16 subjects in two cohorts. The main endpoint was safety assessed at 365 days using ophthalmic and systemic exams. Pseudophakic subjects with geographic atrophy (GA) and severe vision loss were eligible. Low-dose tacrolimus immunosuppression was utilized for 68 days in the peri-implantation period. The implant was delivered to the worst seeing eye with a custom subretinal insertion device in an outpatient setting. A data safety monitoring committee reviewed all results. Results: The treated eyes of all subjects were legally blind with a baseline best-corrected visual acuity (BCVA) of ≤ 20/200. There were no unexpected serious adverse events. Four subjects in cohort 1 had serious ocular adverse events, including retinal hemorrhage, edema, focal retinal detachment, or RPE detachment, which was mitigated in cohort 2 using improved hemostasis during surgery. Although this study was not powered to assess efficacy, treated eyes from four subjects showed an increased BCVA of >5 letters (6-13 letters). A larger proportion of treated eyes experienced a >5-letter gain when compared with the untreated eye (27% vs. 7%; P = not significant) and a larger proportion of nonimplanted eyes demonstrated a >5-letter loss (47% vs. 33%; P = not significant). Conclusions: Outpatient delivery of the implant can be performed routinely. At 1 year, the implant is safe and well tolerated in subjects with advanced dry AMD. Translational Relevance: This work describes the first clinical trial, to our knowledge, of a novel implant for advanced dry AMD.

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.

A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration.

Retinal pigment epithelium (RPE) dysfunction and loss are a hallmark of non-neovascular age-related macular degeneration (NNAMD). Without the RPE, a majority of overlying photoreceptors ultimately degenerate, leading to severe, progressive vision loss. Clinical and histological studies suggest that RPE replacement strategies may delay disease progression or restore vision. A prospective, interventional, U.S. Food and Drug Administration-cleared, phase 1/2a study is being conducted to assess the safety and efficacy of a composite subretinal implant in subjects with advanced NNAMD. The composite implant, termed the California Project to Cure Blindness-Retinal Pigment Epithelium 1 (CPCB-RPE1), consists of a polarized monolayer of human embryonic stem cell-derived RPE (hESC-RPE) on an ultrathin, synthetic parylene substrate designed to mimic Bruch's membrane. We report an interim analysis of the phase 1 cohort consisting of five subjects. Four of five subjects enrolled in the study successfully received the composite implant. In all implanted subjects, optical coherence tomography imaging showed changes consistent with hESC-RPE and host photoreceptor integration. None of the implanted eyes showed progression of vision loss, one eye improved by 17 letters and two eyes demonstrated improved fixation. The concurrent structural and functional findings suggest that CPCB-RPE1 may improve visual function, at least in the short term, in some patients with severe vision loss from advanced NNAMD.

Congenital optic nerve anomaly and migration of subretinal oil: case report and observations in one family.

PURPOSE: To describe a case of optic nerve (ON) anomaly and retinal detachment with extensive subretinal silicone oil after repair of retinal detachment. A three-generation family history of ON anomaly, two generations with detachment, is presented. METHODS: Retrospective chart review. A multigenerational family with ON anomalies and macular detachment. RESULTS: Final repair of retinal detachment was achieved using retinotomy for removal of subretinal 5,000-centistoke silicone oil, gas-fluid exchange, and peripapillary photocoagulation. Silicone oil had been previously used successfully in this eye, yet on subsequent use resulted in subretinal migration. A four patient-three-generation family history of ON anomalies was elicited, and three members were photographed for documentation. CONCLUSION: Optic nerve anomalies and macular detachment present a treatment dilemma because they are associated with poor vision and often a suboptimal visual outcome after surgery. This case demonstrates a large amount of subretinal silicone oil, which migrated over a 2-month period. This case series is a report of a three-generational family demonstrating variable expressivity of ON anomalies complicated by macular detachment in two generations.

Travel to high mountain elevations following vitrectomy with intraocular gas.

PURPOSE: To evaluate the effects and safety of travel by land through high mountainous elevations after surgery in patients who have undergone pars plana vitrectomy with intraocular gas. METHODS: A retrospective cohort study of 75 patients post pars plana vitrectomy with intraocular gas who traveled by land through mountain elevations of up to 3895 feet above sea level within 1 day of surgery. RESULTS: The average rate of ascent through the mountains was 29 ft/min and the maximum theoretical ocular compensation was 0.57 cubic centimeters (cc), which occurred at 4259 feet above sea level. A statistically significant change in postoperative intraocular pressure was found when compared with preoperative (P = 0.010), with two factors influencing this change: the type of gas (C3F8, P = 0.038) and lens status (pseudophakic, P = 0.010), with a mean final intraocular pressure still within the safe range. There were no cases of retinal vascular occlusion, acute elevations of intraocular pressure requiring surgical intervention, or symptomatic visual field loss attributable to elevated intraocular pressure. CONCLUSION: It seems that patients with a complete fill of intraocular gas after pars plana vitrectomy may travel safely by land through mountains with a peak ascent of 3895 feet, final ascent of 2787 feet, and a mean rate of 29 ft/min. These findings can significantly impact patient costs and convenience.