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

Abstract

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.

Regeneration of the zebrafish retinal pigment epithelium after widespread genetic ablation

“…Transplantation of stem cell-derived RPE has emerged as a possibility for treating AMD (12,13), and clinical trials are currently underway (e.g. (14)(15)(16)(17)(18)). An unexplored complementary approach is the development of therapies that stimulate endogenous RPE regeneration.…”

Preclinical safety studies of human embryonic stem cell-derived retinal pigment epithelial cells for the treatment of age-related macular degeneration

“…The progress in human development knowledge and the refinement in hPSC culture and differentiation protocols have brought hPSC cells and their derivatives into the first clinical trials for several diseases, including AMD. [15][16][17][18][19][20] As the use of hPSC and/or their derivatives is reaching patients, multiple efforts are put together aiming to develop tests to assess the safety of the stem cell-derived products. Several groups have shown that hPSC may acquire genetic and/or epigenetic mutations during their culture or differentiation, 26,52 raising some concerns about their use in future cell therapies.…”

Concise Review: Update on Retinal Pigment Epithelium Transplantation for Age-Related Macular Degeneration

“…Kashani et al transplanted 3.5 mm × 6.25 mm sheets of hESC‐derived RPE monolayers into areas of GA in five AMD patients . Since RPE cells are lacking in areas of GA, these experiments explicitly replace lost native RPE in the area of GA.…”

“…There was no correlation between the presence of postoperative pigmentation and postoperative visual improvement, nor did the absence of hyperpigmentation preclude visual improvement. Kashani et al transplanted 3.5 mm × 6.25 mm sheets of hESC-derived RPE monolayers into areas of GA in five AMD patients [36]. Since RPE cells are lacking in areas of GA, these experiments explicitly replace lost native RPE in the area of GA.…”

“…Visual recovery following antivascular endothelial growth factor therapy for CNVs in AMD patients is associated with restoration of the ellipsoid zone, which occurs where the ELM is retained [49]. Kashani four patients (including the patient with marked visual improvement), which may mean that the transplanted RPE cells were integrating with the overlying host photoreceptors [14,36,47]. One may question whether visual improvement is possible in areas of GA, but, as noted above, histopathological studies have demonstrated that some photoreceptor cells lacking inner and outer segments persist in these areas [4,13,14].…”