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      Stem cells as a therapeutic tool for the blind: biology and future prospects

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          Abstract

          Retinal degeneration due to genetic, diabetic and age-related disease is the most common cause of blindness in the developed world. Blindness occurs through the loss of the light-sensing photoreceptors; to restore vision, it would be necessary to introduce alternative photosensitive components into the eye. The recent development of an electronic prosthesis placed beneath the severely diseased retina has shown that subretinal stimulation may restore some visual function in blind patients. This proves that residual retinal circuits can be reawakened after photoreceptor loss and defines a goal for stem-cell-based therapy to replace photoreceptors. Advances in reprogramming adult cells have shown how it may be possible to generate autologous stem cells for transplantation without the need for an embryo donor. The recent success in culturing a whole optic cup in vitro has shown how large numbers of photoreceptors might be generated from embryonic stem cells. Taken together, these threads of discovery provide the basis for optimism for the development of a stem-cell-based strategy for the treatment of retinal blindness.

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          Most cited references69

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          Human induced pluripotent stem cells free of vector and transgene sequences.

          Reprogramming differentiated human cells to induced pluripotent stem (iPS) cells has applications in basic biology, drug development, and transplantation. Human iPS cell derivation previously required vectors that integrate into the genome, which can create mutations and limit the utility of the cells in both research and clinical applications. We describe the derivation of human iPS cells with the use of nonintegrating episomal vectors. After removal of the episome, iPS cells completely free of vector and transgene sequences are derived that are similar to human embryonic stem (ES) cells in proliferative and developmental potential. These results demonstrate that reprogramming human somatic cells does not require genomic integration or the continued presence of exogenous reprogramming factors and removes one obstacle to the clinical application of human iPS cells.
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            Causes and prevalence of visual impairment among adults in the United States.

            To estimate the cause-specific prevalence and distribution of blindness and low vision in the United States by age, race/ethnicity, and gender, and to estimate the change in these prevalence figures over the next 20 years. Summary prevalence estimates of blindness (both according to the US definition of < or =6/60 [< or =20/200] best-corrected visual acuity in the better-seeing eye and the World Health Organization standard of < 6/120 [< 20/400]) and low vision (< 6/12 [< 20/40] best-corrected vision in the better-seeing eye) were prepared separately for black, Hispanic, and white persons in 5-year age intervals starting at 40 years. The estimated prevalences were based on recent population-based studies in the United States, Australia, and Europe. These estimates were applied to 2000 US Census data, and to projected US population figures for 2020, to estimate the number of Americans with visual impairment. Cause-specific prevalences of blindness and low vision were also estimated for the different racial/ethnic groups. Based on demographics from the 2000 US Census, an estimated 937 000 (0.78%) Americans older than 40 years were blind (US definition). An additional 2.4 million Americans (1.98%) had low vision. The leading cause of blindness among white persons was age-related macular degeneration (54.4% of the cases), while among black persons, cataract and glaucoma accounted for more than 60% of blindness. Cataract was the leading cause of low vision, responsible for approximately 50% of bilateral vision worse than 6/12 (20/40) among white, black, and Hispanic persons. The number of blind persons in the US is projected to increase by 70% to 1.6 million by 2020, with a similar rise projected for low vision. Blindness or low vision affects approximately 1 in 28 Americans older than 40 years. The specific causes of visual impairment, and especially blindness, vary greatly by race/ethnicity. The prevalence of visual disabilities will increase markedly during the next 20 years, owing largely to the aging of the US population.
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              Modeling early retinal development with human embryonic and induced pluripotent stem cells.

              Human pluripotent stem cells have the potential to provide comprehensive model systems for the earliest stages of human ontogenesis. To serve in this capacity, these cells must undergo a targeted, stepwise differentiation process that follows a normal developmental timeline. Here we demonstrate the ability of both human embryonic stem cells (hESCs) and induced pluripotent stem (iPS) cells to meet these requirements for human retinogenesis. Upon differentiation, hESCs initially yielded a highly enriched population of early eye field cells. Thereafter, a subset of cells acquired features of advancing retinal differentiation in a sequence and time course that mimicked in vivo human retinal development. Application of this culture method to a human iPS cell line also generated retina-specific cell types at comparable times in vitro. Lastly, altering endogenous signaling during differentiation affected lineage-specific gene expression in a manner consistent with established mechanisms of early neural and retinal cell fate determination. These findings should aid in the investigation of the molecular events governing retinal specification from human pluripotent stem cells.
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                Author and article information

                Journal
                Proc Biol Sci
                RSPB
                royprsb
                Proceedings of the Royal Society B: Biological Sciences
                The Royal Society
                0962-8452
                1471-2954
                22 October 2011
                3 August 2011
                3 August 2011
                : 278
                : 1721
                : 3009-3016
                Affiliations
                [1 ]Nuffield Laboratory of Ophthalmology, simpleUniversity of Oxford , Oxford OX3 9DU, UK
                [2 ]Merton College, simpleUniversity of Oxford , Oxford OX1 4JD, UK
                [3 ]Moorfields Eye Hospital, London EC1V 2PD, UK
                [4 ]Oxford Eye Hospital, Oxford OX3 9DU, UK
                Author notes
                [* ]Author for correspondence ( robert.maclaren@ 123456eye.ox.ac.uk ).
                Article
                rspb20111028
                10.1098/rspb.2011.1028
                3158947
                21813553
                76ba2413-b08b-44ed-9b19-442d51c57f0c
                This journal is © 2011 The Royal Society

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 May 2011
                : 11 July 2011
                Categories
                1001
                33
                58
                133
                Review Articles

                Life sciences
                retinitis pigmentosa,embryonic stem cell,age-related macular degeneration,retinal degeneration,induced pluripotent stem cell,transplantation

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