Stem cell based therapies for age-related macular degeneration: The promises and the challenges

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. AMD is classified as either neovascular (NV-AMD) or non-neovascular (NNV-AMD). Cumulative damage to the retinal pigment epithelium, Bruch's membrane, and choriocapillaris leads to dysfunction and loss of RPE cells. This causes degeneration of the overlying photoreceptors and consequential vision loss in advanced NNV-AMD (Geographic Atrophy). In NV-AMD, abnormal growth of capillaries under the retina and RPE, which leads to hemorrhage and fluid leakage, is the main cause of photoreceptor damage. Although a number of drugs (e.g., anti-VEGF) are in use for NV-AMD, there is currently no treatment for advanced NNV-AMD. However, replacing dead or dysfunctional RPE with healthy RPE has been shown to rescue dying photoreceptors and improve vision in animal models of retinal degeneration and possibly in AMD patients. Differentiation of RPE from human embryonic stem cells (hESC-RPE) and from induced pluripotent stem cells (iPSC-RPE) has created a potentially unlimited source for replacing dead or dying RPE. Such cells have been shown to incorporate into the degenerating retina and result in anatomic and functional improvement. However, major ethical, regulatory, safety, and technical challenges have yet to be overcome before stem cell-based therapies can be used in standard treatments. This review outlines the current knowledge surrounding the application of hESC-RPE and iPSC-RPE in AMD. Following an introduction on the pathogenesis and available treatments of AMD, methods to generate stem cell-derived RPE, immune reaction against such cells, and approaches to deliver desired cells into the eye will be explored along with broader issues of efficacy and safety. Lastly, strategies to improve these stem cell-based treatments will be discussed.

Subretinal implantation of a monolayer of human embryonic stem cell-derived retinal pigment epithelium: a feasibility and safety study in Yucatán minipigs

“…Christiansen et al elaborated this sensitive technique and were able to provide reliable data on the electrophysiologic dependencies of different subretinal materials [18,27]. Although we had no robust mfERG setup in place and would endorse including mfERG in future studies, we feel confident regarding the biocompatibility of the material with and without cells due to our experience with the optokinetic nystagmus and superior colliculus recordings in the RCS rat (data submitted to FDA with an Investigational New Drug submission; this aspect is also discussed in a recent review article by our group [28]). We observed normal INL structure and thickness in most (60 %) eyes, focal implant-related disruption in some (30 %) cases and some ONL thinning in the implantation area in the majority (80 %) of eyes.…”

Let There Be Light: Gene and Cell Therapy for Blindness

“…A human phase I/II clinical trial will evaluate the safety and tolerability of this tissueengineering product (TEP) in patients with gyrate atrophy. 101,109 The proof of concept with this TEP has been reported in RCS rats and in Yucatan pigs. 101,110 As human iPSCs can be obtained directly from the patient, they have the advantage of being autologous and therefore less immunogenic than ESCs for future cell transplantation studies.…”

Langmuir-Schaefer film deposition onto honeycomb porous films for retinal tissue engineering

“…Specifically, the photoreceptors constantly undergo a renewal process where the tips of the photoreceptors containing a number of radical species, photo-damaged proteins and lipids are eliminated by the clearing action of RPE [10,57]. In this context, the assessment of the phagocytic capacity of RPE towards POS can be a valuable tool to evaluate the functionality of RPE cells cultured in vitro [8,14,[58][59][60]. In spite of clear morphological differences between epithelia on LS-and dip-coated scaffolds, dip-coated membranes showing more fusiform RPE cells typically associated with less mature phenotype [61], cells with phagocytic activity could be detected on all materials, regardless of the coating type.…”