Retinal Pigment Epithelium Replacement Therapy for Age-Related Macular Degeneration: Are We There Yet?

Abstract

Pluripotent stem cells (PSCs) are a potential replacement tissue source for degenerative diseases. Age-related macular degeneration (AMD) is a blinding disease triggered by degeneration of the retinal pigment epithelium (RPE), a monolayer tissue that functionally supports retinal photoreceptors. Recently published clinical and preclinical studies have tested PSC-derived RPE as a potential treatment for AMD. Multiple approaches have been used to manufacture RPE cells, to validate them functionally, to confirm their safety profile, and to deliver them to patients either as suspension or as a monolayer patch. Since most of these studies are at an early regulatory approval stage, the primary outcome has been to determine the safety of RPE transplants in patients. However, preliminary signs of efficacy were observed in a few patients. Here, we review the current progress in the PSC-derived RPE transplantation field and provide a comparative assessment of various approaches under development as potential therapeutics for AMD.

Keywords: cell therapy; clinical grade; induced pluripotent stem cells; patch; pluripotent stem cells; retinal degeneration; retinal pigment epithelium.

FIGURE 1

Schematic of various ongoing and planned RPE-transplant approaches. Left panels show a fundus view of the transplant. Right panels show how transplants (purple) would be integrated into the sub-retinal space, their possible impact on retina and choroid and the various scaffold materials. (A) Schwartz et al. injected ESC-RPE cell suspension in the sub-macular region. ESC-RPE cells in suspension do not form a polarized monolayer but stay as a bolus of rounded non-polarized cells in the sub-macular region (5). (B) Da Cruz et al. transplanted an ESC-RPE patch over the area of acute choroidal neovascularization (CNV). This 3×6 mm transplant was intended as an actual “patch” over the area of acute CNV. The RPE-patch helps stop CNV and rescue photoreceptors that may not have degenerated in these specific patients (8). (C) Kashani et al. used an ESC-RPE patch on a parylene scaffold, transplanted in the area of geographic atrophy. Change in fixation point to over the area of the ESC-RPE patch was observed in three patients suggesting that the RPE-patch was able to recover the activity of a few photoreceptors in the transplanted region (9). (D) Mandai et al. tested the first autologous iPSC-RPE patch in an acute wet AMD patient. This patch was transplanted in a macular region that was fibrotic due to chronic vessel leakage. One year follow up in this patient revealed the absence of new leaks (10). (E) Sharma et al. propose to transplant autologous iPSC-RPE patch at the border of geographic atrophy lesion. This patch is intended to cover parts of the transition zone where the photoreceptors are still alive to slow down or halt the expansion of GA lesion (12). (F) M’Barek et al. propose to test a gelatin embedded ESC-RPE patch an amniotic membrane in patients with Leber congenital amaurosis (LCA). This patch will be transplanted on top of dysfunctional native RPE cells such that over the long term the new RPE-patch will integrate into the host RPE monolayer in place of diseased cells.