Review
Development of human embryonic stem cell therapies for age-related macular degeneration

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Highlights

  • Age-related macular degeneration (AMD) is the leading cause of vision loss in older adults. Recent research for treating AMD has focused on replacing the retinal pigment epithelium (RPE), a monolayer of cells vital to photoreceptor cell health

  • Various methods are used to differentiate and purify RPE from human embryonic stem cells, and their efficacy as treatments are being tested in existing and forthcoming clinical trials.

Age-related macular degeneration (AMD) is the leading cause of vision loss in older adults and ultimately leads to the death of photoreceptor cells in the macular area of the neural retina. Currently, treatments are only available for patients with the wet form of AMD. In this review, we describe recent approaches to develop cell-based therapies for the treatment of AMD. Recent research has focused on replacing the retinal pigment epithelium (RPE), a monolayer of cells vital to photoreceptor cell health. We discuss the various methods used to differentiate and purify RPE from human embryonic stem cells (HESC), and describe the surgical approaches being used to transplant these cells in existing and forthcoming clinical trials.

Section snippets

Age-related macular degeneration and the retinal pigment epithelium

AMD is the most common cause of blindness in the developed world [1] and, with increasing life expectancy, the incidence of this disease is set only to increase in the future. Degeneration of macular photoreceptors leads to the loss of high-acuity central vision (Figure 1), which is required for fine detailed tasks, such as reading, driving, and recognising faces. The underlying cause of AMD stems from the loss of, or defects within, the RPE, a single monolayer of highly specialised cells found

Current and experimental treatments for AMD

Several treatments are available for patients with wet AMD, who account for approximately 10% of the total AMD population. Anti-VEGF treatments can stabilise wet AMD by reducing blood vessel growth and preventing further fluid accumulation 6, 7, whereas clinical treatments, such as surgical ablation of neovascular membranes, photodynamic therapy to seal leaky blood vessels or brachytherapy, where radiation therapy is used to destroy new vessels, can prevent progression of the disease. However,

Retinal degeneration and cell transplantation

Given the high number of patients with AMD and the length, complexity, and complications of the experimental surgical procedures described above, an ideal solution would utilise a preprepared source of tissue for transplant. Many possible cell types have been tested in an animal model of retinal degeneration, the Royal College of Surgeons (RCS) rat. Loss of vision in this animal is caused by a naturally occurring mutation in c-mer proto-oncogene tyrosine kinase (MERTK), a protein essential for

Human embryonic stem cells

In recent years, developments in ESC technologies have yielded novel sources of cells for use in AMD cellular therapy (Figure 4). HESCs have the potential to treat a variety of degenerative diseases and are an extremely attractive prospect for use in stem cell therapies owing to their ability to self-renew indefinitely while maintaining a stable undifferentiated state. HESCs can be isolated from the inner cell mass of the human blastocyst at approximately 5 days postfertilisation and maintained

iPSCs and RPE cell generation

iPSCs are stem cells derived from fully differentiated somatic cells, such as fibroblasts or blood cells. Somatic cells can be reprogrammed to pluripotency in vitro, typically using a combination of embryonic transcription factors 81, 82, 83 (Figure 4). iPSCs are similar to ESCs with regards to morphology, transcriptional profiling, pluripotency, and their potential to differentiate into the three germ layers [84]. The pluripotency of iPSCs has enabled researchers to differentiate reprogrammed

Acknowledgements

The authors would like to thank Shazeen Hasan and Sakina Gooljar for providing images of the HESC-RPE patch. This work was supported by funding from The London Project to Cure Blindness, The Medical Research Council (MRC) UK, The Californian Institute of Regenerative Medicine (CIRM), Fight for Sight UK, The Lincy Foundation, The Macular Society, and The National Institute for Health Research.

Glossary

Differentiation
commitment of a cell to a more specialised cell type.
Drusen
deposits of extracellular material (proteins and lipids) that form between the RPE and Bruch's membrane, which appear as distinct yellow–white spots. The exact etiology of this material is unknown. Although observed in normal ageing eyes, they are thought to be an early sign of macular degeneration.
Embryonic stem cell (ESC)
a pluripotent cell harvested from the inner cell mass of a pre-implantation embryo at the blastocyst

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