Photoreceptor cell replacement in macular degeneration and retinitis pigmentosa: A pluripotent stem cell-based approach

Abstract

The human retina fails to regenerate and cell-based therapies offer options for treatment of blinding retinal diseases, such as macular degeneration and retinitis pigmentosa (RP). The last decade has witnessed remarkable advances in generation of retinal cells and retinal tissue from human pluripotent stem cells (PSCs). The development of 3D culture systems allowing generation of human retinal organoids has substantially increased the access to human material for future clinical applications aiming at replacing the lost photoreceptors in retinal degenerative diseases. This review outlines the advances that have been made toward generation and characterization of transplantable photoreceptors from PSCs and summarizes the current status of PSC-based preclinical studies for photoreceptor replacement conducted in animal models. Considering the recent turning point in our understanding of donor photoreceptor integration, this review focuses on the most crucial obstacles that hinder the photoreceptor replacement, discusses the most promising strategies to overcome them in the future, and provides a perspective on the approaching advancement in the application of PSC technology for treatment of photoreceptor degenerative diseases.

KIT ligand protects against both light-induced and genetic photoreceptor degeneration

“…Currently, one of the major challenges for the field of retinal degenerative diseases is to provide strategies to prevent or delay the onset of photoreceptor cell loss. Several approaches are currently under investigation to treat vision loss in patients suffering from retinal degenerations, including retinal prostheses implants, stem cell transplants and gene therapy (Gagliardi et al, 2019;Scholl et al, 2016). Although gene therapy has recently been approved for a specific causative mutation (RPE65) (Russell et al, 2017), there are still no broadly applicable and efficacious treatments available to prevent or cure vision loss caused by photoreceptor degeneration.…”

Establishment of a Rapid, Lesion-Controllable Retinal Degeneration Model in Monkey for Preclinical Stem Cell Therapy

“…With the successful induction of three-dimensional (3D) retinal organoids including neural retina and RPE from hPSCs [9,10,33,34], stem cell therapy, such as retinal cell transplantation, has been regarded as a potential treatment for RDs [5,6]. Thus, carrying out the experiments in vivo are necessary for the safety evaluation and for the detailed analyses of e cacy, such as migration, integration or anatomy of grafts and the loss or recovery of focal retinal function.…”

“…Despite various therapeutic modalities developed to slow cell death progress or restore their functions [3][4][5], there is no cure for these diseases so far. Retinal cell transplantation has been regarded as a potential treatment to replace the damaged cells, and to restore their structure and function as well [6]. With the rapid development of human pluripotent stem cell (hPSC) technology and successful reproduction of retinal cells and tissues with hPSCs [7][8][9][10][11][12], the bottleneck of retinal grafts, cell or tissue donor issue, has been largely solved.…”

The primate model for understanding and restoring vision

“…We also used ex vivo NHP retinal explants to assess the efficacy of the PRIMA photovoltaic retinal prosthesis (17). The recent development of retinal organoids from induced pluripotent stem cells (iPSCs) has extended the interest in in vitro studies by providing an unlimited source of human retinal cells, with the additional possibility of generating tissues from patients affected by specific gene mutations (72,(74)(75)(76)(77). Such in vitro/ex vivo retinal models will allow an essential validation step prior to in vivo NHP studies and thus reduce the number of animals in preclinical studies.…”