Strategies of pluripotent stem cell-based therapy for retinal degeneration: update and challenges

Regenerative medicine for retinal degeneration in the outer layer of the retina has entered the practical stage given recent progress in that field utilizing advantageous aspects of the retina as a target of regenerative medicine. Next-generation therapies for expanding indications are progressing since the safety and efficacy of embryonic stem cell (ESC)/induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) transplantation have been confirmed to a certain extent in clinical studies globally for age-related macular degenerations. The development of next-generation therapies using retinal sheet derived from iPSCs for expanding indications is progressing. However, several issues in the popularization of retinal regenerative medicine due to the complex characteristics of the retina and cell products remain. Therefore, the application of an alternative strategy of regenerative medicine, such as induction of autologous retinal cells from somatic cells via a direct reprogramming system, may also be useful in the future. Stem cell-based therapy for retinal degeneration is transitioning from the research stage to the clinical stage and is being developed as a treatment across the globe. In clinical studies on induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) transplantation, the safety of the technique has started to clarify, and clinical study on further advances such as the long-desired transplantation of iPSC-derived retina to treat retinitis pigmentosa (RP) has begun. Ophthalmologists are now working closely with basic researchers to incorporate new technology areas with a synergy that is anticipated to realize the practical application of stem cell-based therapy for retinal degeneration. Stem cell-based therapy for retinal degeneration is transitioning from the research stage to the clinical stage and is being developed as a treatment across the globe. In clinical studies on induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) transplantation, the safety of the technique has started to clarify, and clinical study on further advances such as the long-desired transplantation of iPSC-derived retina to treat retinitis pigmentosa (RP) has begun. Ophthalmologists are now working closely with basic researchers to incorporate new technology areas with a synergy that is anticipated to realize the practical application of stem cell-based therapy for retinal degeneration. AMD is one of the leading causes of severe central vision loss in the elderly population worldwide. AMD is induced via sequential damage of retinal pigment epithelium (RPE), Bruch's membrane (BM), choroidal membrane, and photoreceptors due to pathological changes with age. The global prevalence of AMD is 8.7% and is estimated to affect ~288 million individuals globally by 2040. The advanced stages of AMD are categorized into two forms: nonneovascular (dry, nonexudative, or geographic) and neovascular (wet or exudative). Dry AMD is characterized by geographic atrophy of the outer retina, including the RPE, photoreceptors, and choriocapillaris, resulting in gradual retinal cell loss and decreased visual acuity. In wet AMD, choroidal neovascularization (CNV) causes exudative changes involving subretinal leakage of blood, lipids, fluids, and the formation of fibrous scars. a collagenous tissue found between RPE and choroidal membrane. BM functions as a basal membrane for RPE. BM thickens with age, slowing the transport of metabolites, leading to the formation of drusen, a metabolite deposit that causes pathological changes in AMD. a technology that uses the interference of light to take high-resolution, high-speed images of the internal structure of the retina. It can be used for noncontact, noninvasive imaging by irradiating near-infrared light and obtaining a high-resolution image of the retina. a neuroepithelial cell in the retina that initiates phototransduction by converting the light signal into the electoral response. Photoreceptor cells have an outer segment that functions as a light receptor and an inner segment that involves organelles to maintain the function of the cell. Photoreceptor cells are categorized into two types, cones and rods. Cones are localized in the macula and serve color vision under bright circumstances. By contrast, rods are found in the macular region and are used for monochromatic vision under dark circumstances. The human retina contains ~six million cones and ~100 million rods. RPE is the pigmented cell layer below the neural retina. RPE is attached to the BM and forms a retina–blood barrier between the retina and choroidal membrane. RPE comprises a single layer of hexagonal cells and serves several functions, such as light absorption, epithelial transport, spatial ion buffering, visual cycle, phagocytosis, secretion, and immune modulation. RP is a group of hereditary diseases that is prevalent in 3000–4000 individuals worldwide. RP is a Mendelian disease that can be autosomal dominant, autosomal recessive, or X-linked. Patients with RP initially develop night blindness and visual field impairment around age 20–30 years due to the loss of rods, followed by a decrease of visual acuity and loss of color vision around age 40–60 years due to the degeneration of cones.