Repair of the degenerate retina by photoreceptor transplantation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 1; pp. 354 - 359
• Main Authors: Barber, Amanda C., Hippert, Claire, Duran, Yanai, West, Emma L., Bainbridge, James W. B., Warre-Cornish, Katherine, Luhmann, Ulrich F. O., Lakowski, Jorn, Sowden, Jane C., Ali, Robin R., Pearson, Rachael A.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences 02.01.2013; National Acad Sciences
• Subjects: Animals; Biological and medical sciences; Biological Sciences; Blindness; Blotting, Western; Cell Count; Cell transplantation; Cyclic Nucleotide Phosphodiesterases, Type 6 - metabolism; Disease models; Disease progression; Eye and associated structures. Visual pathways and centers. Vision; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Gliosis; GTP-Binding Protein alpha Subunits - genetics; GTP-Binding Protein alpha Subunits - metabolism; Intermediate Filament Proteins - metabolism; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Microscopy, Electron, Transmission; Nerve Tissue Proteins - metabolism; Neurons; Neuropsychology; Night Blindness - genetics; Night Blindness - surgery; Optic Atrophy, Hereditary, Leber - genetics; Optic Atrophy, Hereditary, Leber - surgery; Peripherins; Photoreceptors; Retina; Retinal degeneration; Retinal diseases; Retinal Rod Photoreceptor Cells - transplantation; Retinal Rod Photoreceptor Cells - ultrastructure; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - surgery; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - metabolism; Rodents; Stem cells; Transducin - genetics; Transducin - metabolism; Transplantation; Transplants & implants; Treatment Outcome; Vertebrates: nervous system and sense organs; Eye; Visual system; stem cells; retinal degeneration; Gliosis; Stem cell; Photoreceptor; Retina; Degeneration; Transplantation; Repair
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1212677110

Despite different aetiologies, age-related macular degeneration and most inherited retinal disorders culminate in the same final common pathway, the loss of photoreceptors. There are few treatments and none reverse the loss of vision. Photoreceptor replacement by transplantation is proposed as a broad treatment strategy applicable to all degenerations. Recently, we demonstrated restoration of vision following rod-photoreceptor transplantation into a mouse model of stationary night-blindness, raising the critical question of whether photoreceptor replacement is equally effective in different types and stages of degeneration. We present a comprehensive assessment of rod-photoreceptor transplantation across six murine models of inherited photoreceptor degeneration. Transplantation is feasible in all models examined but disease type has a major impact on outcome, as assessed both by the morphology and number of integrated rod-photoreceptors. Integration can increase (Prph2⁺/∆³⁰⁷), decrease (Crb1rd⁸/rd⁸ Gnat1⁻/⁻, Rh⁻/⁻), or remain constant (PDE6βrd¹/rd¹, Prph2rd²/rd²) with disease progression, depending upon the gene defect, with no correlation with severity. Robust integration is possible even in late-stage disease. Glial scarring and outer limiting membrane integrity, features that change with degeneration, significantly affect transplanted photoreceptor integration. Combined breakdown of these barriers markedly increases integration in a model with an intact outer limiting membrane, strong gliotic response, and otherwise poor transplantation outcome (Rho⁻/⁻), leading to an eightfold increase in integration and restoration of visual function. Thus, it is possible to achieve robust integration across a broad range of inherited retinopathies. Moreover, transplantation outcome can be improved by administering appropriate, tailored manipulations of the recipient environment.