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

Abstract

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.

Survival of an HLA-mismatched, bioengineered RPE implant in dry age-related macular degeneration

“…Due to the extreme severity of GA in this subject, it is also not surprising that there was no improvement in vision, but the histopathologic and clinical persistence of RPE cells suggests that a therapeutic effect might be possible in less advanced disease. Clinical examination of all remaining subjects in the ongoing study ( Kashani et al., 2021 ) also demonstrates persistent pigmentation of the implant through 1 year, supporting the histologic findings in the one subject presented here.…”

Changes in best-corrected visual acuity in patients with dry age-related macular degeneration after stem cell transplantation: systematic review and meta-analysis

“…Three articles [ 34 , 42 , 43 ] were based on the same dataset; only the latest article [ 34 ] was included. Among these studies, one [ 36 ] was a randomised prospective clinical trial, three [ 34 , 35 , 40 ] were non-randomised prospective clinical trials, one [ 38 ] was a multicentre prospective clinical trial, and five [ 23 , 33 , 37 , 39 , 41 ] were prospective clinical trials. In total, 102 patients with dry AMD who underwent SCT were included in this meta-analysis.…”

Stem cell-derived retinal pigment epithelium transplantation in age-related macular degeneration: recent advances and challenges

“…In no case has there been reports of any clinically detectable signs of vitritis, retinitis, vasculitis, or choroiditis despite the absence of HLA matching in these studies [16,18,44 ▪▪ ,45]. In one study, there was <50% HLA matching between the donor and host HLA loci in all subjects [46 ▪▪ ]. Nevertheless, there was no evidence of systemic humoral immunity or clinical evidence of immune response as assessed by clinical signs of vitritis, retinitis, vasculitis, or choroiditis in any subject through one year of follow-up (Fig.…”

“…Nevertheless, there was no evidence of systemic humoral immunity or clinical evidence of immune response as assessed by clinical signs of vitritis, retinitis, vasculitis, or choroiditis in any subject through one year of follow-up (Fig. 1) [46 ▪▪ ]. A total of 4 of 15 subjects demonstrated macular edema at some time point during their postoperative course which was attributable to typical postoperative cystoid macular edema that was improved after silicone oil removal [46 ▪▪ ].…”

“…The above studies illustrate that a systematic and consensus method of detecting both clinical and subclinical immune response in subjects with any form of cell-based intraocular transplantation would be very helpful. Most studies report a combination of clinical exam, imaging and diagnostic labbased assays but there is no consensus on what constitutes a significant immunologic response in the absence of clinical symptoms of vision loss or clinical signs such as aqueous cell, vitritis, retinitis, choroiditis, vasculitis, and possibly macular edema [18,32 ▪▪ ,46 ▪▪ ]. Even in the latter case, there is no consensus or criteria by which to distinguish typical postoperative cystoid macular edema that is a common occurrence after almost any form of intraocular surgery versus macular edema that would arise from a targeted immune response to donor stem cell-derived tissue.…”