Cell-Based Therapy for Degenerative Retinal Disease

PRs and RPE cells can be grown from embryonic and induced pluripotent stem cells. 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. PR transplants can integrate with host retinae even in late stages of retinal degeneration. 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. 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. 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. 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. 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.