Pluripotent stem cell therapy for retinal diseases

Abstract

Pluripotent stem cells (PSCs), which include human embryonic stem cells (hESCs) and induced pluripotent stem cell (iPSC), have been used to study development of disease processes, and as potential therapies in multiple organ systems. In recent years, there has been increasing interest in the use of PSC-based transplantation to treat disorders of the retina in which retinal cells have been functionally damaged or lost through degeneration. The retina, which consists of neuronal tissue, provides an excellent system to test the therapeutic utility of PSC-based transplantation due to its accessibility and the availability of high-resolution imaging technology to evaluate effects. Preclinical trials in animal models of retinal diseases have shown improvement in visual outcomes following subretinal transplantation of PSC-derived photoreceptors or retinal pigment epithelium (RPE) cells. This review focuses on preclinical studies and clinical trials exploring the use of PSCs for retinal diseases. To date, several phase I/II clinical trials in patients with age-related macular degeneration (AMD) and Stargardt disease (STGD1) have demonstrated the safety and feasibility of PSC-derived RPE transplantation. Additional phase I/II clinical trials using PSC-derived RPE or photoreceptor cells for the treatment of AMD, STGD1, and also retinitis pigmentosa (RP) are currently in the pipeline. As this field continues to evolve, additional technologies may enhance PSC-derived cell transplantation through gene-editing of autologous cells, transplantation of more complex cellular structures such as organoids, and monitoring of transplanted cells through novel imaging technologies.

Keywords: Retinitis pigmentosa (RP); age-related macular degeneration (AMD); embryonic stem cell (ESC); induced pluripotent stem cell (iPSC); retinal organoid.

Figure 1

Photoreceptor and retinal pigment epithelium (RPE) replacement. (A) Normal retinal anatomy is characterized by a layer of photoreceptor cells positioned adjacent to the RPE layer that is supported by Bruch’s membrane. For simplicity, only one layer of photoreceptor cell nuclei is depicted. (B) In degenerative retinal diseases, the loss of photoreceptor and RPE cells occurs within areas of retinal atrophy. Atrophic areas typically expand in size over time. Transition zones occur at the boundaries between atrophic and non-atrophic areas, wherein photoreceptor cells exist that are only partially damaged. The partially damaged photoreceptors, with intact cell bodies, are thought to be amenable to functional repair provided that the RPE layer is replenished. Replenishment of the RPE layer is required to re-establish structural, metabolic, and nutritional support that photoreceptors normally require for survival and optimal function. (C) Transplantation of stem cell-derived RPE cells (green) into the transition zone could lead to functional reactivation of overlying photoreceptor cells. (D) Regeneration of photoreceptor cells within areas of atrophy will likely require transplantation of both photoreceptor and RPE cells (green), as RPE cells are critical for the long-term survival and function of photoreceptor cells.