Phase I/II human clinical trials of stem cell-derived RPE for age-related macular degeneration and Stargardt disease have been completed successfully, and 18 clinical trials of cell-based therapy for retinal degenerative disease are currently underway.

Physical barriers, such as the external limiting membrane, and biochemical properties of the extracellular matrix, such as disease-related changes in Bruch's membrane and the interphotoreceptor matrix, may limit transplanted cell integration with host tissue.

PR transplants can integrate with host retinae even in late stages of retinal degeneration.

Transplanted stem cell-derived PRs and RPE cells have been shown to integrate with host retinae and restore visual function in preclinical models of human retinal degenerative disease.

PRs and RPE cells can be grown from embryonic and induced pluripotent stem cells.

Stem cell-derived retinal pigment epithelium (RPE) and photoreceptors (PRs) have restored vision in preclinical models of human retinal degenerative disease. This review discusses characteristics of stem cell therapy in the eye and the challenges to clinical implementation that are being confronted today. Based on encouraging results from Phase I/II trials, the first Phase II clinical trials of stem cell-derived RPE transplantation are underway. PR transplant experiments have demonstrated restoration of visual function in preclinical models of retinitis pigmentosa and macular degeneration, but also indicate that no single approach is likely to succeed in overcoming PR loss in all cases. A greater understanding of the mechanisms controlling synapse formation as well as the immunoreactivity of transplanted retinal cells is urgently needed.

Purchase access to all full-text HTML articles for 6 or 36 hr at a low cost. Click here to explore this opportunity.

To read this article in full you will need to make a payment

Non cell-autonomous reprogramming of adult ocular progenitors: generation of pluripotent stem cells without exogenous transcription factors.

Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA.

Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds.

Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2.

Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2.

Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts.

Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space.

Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types.

Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance.

The challenge of immunogenicity in the quest for induced pluripotency.

Vulnerability of allogeneic retinal pigment epithelium to immune T-cell-mediated damage in vivo and in vitro.

Analysis of immune deviation elicited by antigens injected into the subretinal space.

Immunosuppressive properties of the pigmented epithelial cells and the subretinal space.

Chondroitinase ABC treatment enhances synaptogenesis between transplant and host neurons in model of retinal degeneration.

RhoA inactivation prevents photoreceptor axon retraction in an in vitro model of acute retinal detachment.

Cyclic AMP prevents retraction of axon terminals in photoreceptors prepared for transplantation: an in vitro study.

The new paradigm: retinal pigment epithelium cells generated from embryonic or induced pluripotent stem cells.

A cell culture medium that supports the differentiation of human retinal pigment epithelium into functionally polarized monolayers.

A method to enhance cell survival on Bruch's membrane in eyes affected by age and age-related macular degeneration.

Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium.

Autologous transplantation of the retinal pigment epithelium and choroid in the treatment of neovascular age-related macular degeneration.

The use of progenitor cell/biodegradable MMP2-PLGA polymer constructs to enhance cellular integration and retinal repopulation.

Survival, migration and differentiation of retinal progenitor cells transplanted on micro-machined poly(methyl methacrylate) scaffolds to the subretinal space.

Transplantation of retinal pigment epithelial cells and immune response in the subretinal space.

Subretinal implantation of retinal pigment epithelial cells derived from human embryonic stem cells: improved survival when implanted as a monolayer.

Human RPE stem cells grown into polarized RPE monolayers on a polyester matrix are maintained after grafting into rabbit subretinal space.

Long-term safety and efficacy of human-induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa.

Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFbeta and Wnt signaling.

Stem cell based therapies for age-related macular degeneration: The promises and the challenges.

X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations.

Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years.

Phagocytosis of photoreceptor outer segments by transplanted human neural stem cells as a neuroprotective mechanism in retinal degeneration.

Human induced pluripotent stem cells are a novel source of neural progenitor cells (iNPCs) that migrate and integrate in the rodent spinal cord.

Cell transplantation to arrest early changes in an ush2a animal model.

Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk.

Novel mutations in MERTK associated with childhood onset rod-cone dystrophy.

Characterisation of severe rod-cone dystrophy in a consanguineous family with a splice site mutation in the MERTK gene.

Trophic factors in the pathogenesis and therapy for retinal degenerative diseases.

Transplantation of Schwann cell line clones secreting GDNF or BDNF into the retinas of dystrophic Royal College of Surgeons Rats.

Cone photoreceptor recovery after experimental detachment and reattachment: an immunocytochemical, morphological, and electrophysiological study.

Adaptive optics microperimetry and OCT images show preserved function and recovery of cone visibility in macular telangiectasia type 2 retinal lesions.

How many cones are required to ‘see?’: lessons from Stargardt's macular dystrophy and from modeling with degenerate photoreceptor arrays.

Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor.

Cone and rod photoreceptor transplantation in models of the childhood retinopathy Leber congenital amaurosis using flow-sorted Crx-positive donor cells.

A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene.

Pharmacological disruption of the outer limiting membrane leads to increased retinal integration of transplanted photoreceptor precursors.

Targeted disruption of outer limiting membrane junctional proteins (Crb1 and ZO-1) increases integration of transplanted photoreceptor precursors into the adult wild-type and degenerating retina.

Swine cone and rod precursors arise sequentially and display sequential and transient integration and differentiation potential following transplantation.

Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation.

Targeting of GFP to newborn rods by Nrl promoter and temporal expression profiling of flow-sorted photoreceptors.

Regressive and reactive changes in the connectivity patterns of rod and cone pathways of P23H transgenic rat retina.

The culture and maintenance of functional retinal pigment epithelial monolayers from adult human eye.

Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives.

Transplantation of photoreceptors derived from human Muller glia restore rod function in the P23H rat.

Late-stage neuronal progenitors in the retina are radial Muller glia that function as retinal stem cells.

Use of a synthetic xeno-free culture substrate for induced pluripotent stem cell induction and retinal differentiation.

Derivation and comparative assessment of retinal pigment epithelium from human embryonic stem cells using transcriptomics.

Blood-derived human iPS cells generate optic vesicle-like structures with the capacity to form retinal laminae and develop synapses.

Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation.

Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies.

Improvement and decline in vision with gene therapy in childhood blindness.

Plasticity of the human visual system after retinal gene therapy in patients with Leber's congenital amaurosis.

The natural history of Stargardt disease with specific sequence mutation in the ABCA4 gene.

Wong, W.L. et al. (2014) Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040, a systematic review and meta-analysis. Lancet Glob Health 2, e106–116

Glossary

a hereditary visual disorder characterized by absence of color vision, decreased visual acuity, and photophobia (sensitivity to light).

age-related macular degeneration is the leading cause of severe central visual loss (associated with loss of face recognition and of the ability to read or drive a motor vehicle) in persons over age 60 years in the industrialized world. It is associated with damage to photoreceptors, retinal pigment epithelial cells, Bruch's membrane, and the choriocapillaris.

an inhibitory retinal interneuron that makes synaptic connections in the inner plexiform layer with bipolar and/or ganglion cells.

a retinal interneuron that receives input from photoreceptors and transmits signals to retinal ganglion cells.

collagenous tissue that separates retinal pigment epithelial cells from the subjacent vascular layer, termed the choroid. By convention, Bruch's membrane is described as a pentalaminar structure comprising the retinal pigment epithelium basement membrane, an inner collagenous layer, a discontinuous elastic layer, an outer collagenous layer, and the choroidal capillary basement membrane.

retinal photoreceptors that mediate color vision and function optimally in bright light (i.e., photopic conditions). Cones are densely packed in the foveola, where they mediate high-acuity vision needed for reading, face recognition, and tasks such as sewing. Three types: S-cones (sensitive to short-wavelength light), M-cones (sensitive to medium-wavelength light), and L-cones (sensitive to long-wavelength light). The three types of cones mediate trichromatic vision in humans. The human retina contains ∼6 million cones.

retinal dystrophy associated with a mutation in the crumbs homolog 1 gene (Crb1) which results in absence of the Crb1 protein in the outer limiting membrane.

a region within the ellipsoid layer of the photoreceptor inner segments that is formed primarily by mitochondria.

the layer of the retina consisting of retinal ganglion cells and displaced amacrine cells. The retinal ganglion cell receives synaptic input from bipolar cells and amacrine cells and transmits information from the retina to the thalamus, hypothalamus, and midbrain.

refers to the advanced stage of age-related macular degeneration characterized by well-circumscribed areas of photoreceptor death associated with death of subjacent retinal pigment epithelium and atrophy of subjacent choroidal capillaries. When areas of GA involve the fovea, high-acuity vision is lost.

the inner nuclear layer of the retina contains the cell bodies of bipolar, horizontal, and amacrine neurons as well as Müller cell bodies.

a thin membrane at the junction of the vitreous body and the retina comprising the basement membranes of Müller cells and accessory glial cells as well as fibrils from the vitreous cortex.

a layer of the retina containing synaptic connections between bipolar cells, ganglion cells, and amacrine cells.

the part of the photoreceptor cell that contains abundant mitochondria, endoplasmic reticulum, Golgi complex, ribosomes, and a cilium that connects the inner and outer segment as well as a synaptic terminal at which contact with horizontal cells is made.

a diagnostic technique used to assess visual function of a specific area of the retina.

the most common glial cell type present in the vertebrate retina.

the retinal nerve fiber layer comprises the axons of retinal ganglion cells.

a cup-like outgrowth of the embryonic brain that develops into the retina.

contains cell bodies of the rod and cone photoreceptors in the retina.

a layer of the retina containing synaptic connections between photoreceptors, bipolar cells, and horizontal cells.

the part of the photoreceptor that contains light-sensitive pigment. Photoreceptors shed outer segment tips on a daily basis.

a type III intermediate filament protein that is present in rod and cone photoreceptor outer segment discs. Mutations in peripherin cause retinal degeneration in the rds mouse associated with abnormal rod and cone outer segment formation, which results in slowly progressive rod and cone degeneration.

a specialized retinal neuron that mediates phototransduction – the conversion of electromagnetic radiation into membrane potential changes resulting in altered neurotransmitter release from photoreceptor synaptic terminals.

the spatial arrangement of photoreceptors in the retina.

a pigmented cell monolayer that is attached to Bruch's membrane and is intimately associated with the photoreceptor outer segments. RPE cells normally contain melanin and have hexagonal morphology. They are polarized with apical villous processes that envelop photoreceptor outer segments and mediate phagocytosis of shed outer segment tips on a daily basis. RPE cells phagocytose these tips.

a group of inherited disorders associated with progressive photoreceptor degeneration and blindness. Inheritance of RP can be autosomal recessive, autosomal dominant, or X-linked. In typical RP, rods die first, followed by cone death. RP can be associated with extraocular findings such as deafness (Usher syndrome), obesity (Bardet–Biedl syndrome), or cardiac conduction defects (Kearns–Sayre syndrome).

the light-sensitive G protein-coupled receptor present in rod photoreceptors that consists of a protein, scotopsin, bound to retinal.

retinal photoreceptor that mediates vision under dim light (scotopic) conditions. In contrast to cones, rods have only one type of photosensitive pigment, rhodopsin. The human retina contains ∼120 million rods.

a transgenic rat that expresses a mutant rhodopsin similar to that found in human patients with retinitis pigmentosa. The S334ter mutation causes the formation of a truncated rhodopsin that is not trafficked to the outer segments.

contains vitreous humor, a clear gel that occupies the space between the crystalline lens and the retina. Vitreous humor may play a role in ion buffering in the retina.