title: Repair of the degenerate retina by photoreceptor transplantation.
abstract: 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(+/Δ307)), decrease (Crb1(rd8/rd8), Gnat1(-/-), Rho(-/-)), or remain constant (PDE6β(rd1/rd1), Prph2(rd2/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.
authors.affiliation: Department of Genetics,  University College London Institute of Ophthalmology, London EC1V 9EL,  United Kingdom.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Barber
authors.forename: Claire
authors.initials: C
authors.lastname: Hippert
authors.forename: Yanai
authors.initials: Y
authors.lastname: Duran
authors.forename: Emma L
authors.initials: EL
authors.lastname: West
authors.forename: James W B
authors.initials: JW
authors.lastname: Bainbridge
authors.forename: Katherine
authors.initials: K
authors.lastname: Warre-Cornish
authors.forename: Ulrich F O
authors.initials: UF
authors.lastname: Luhmann
authors.forename: Jorn
authors.initials: J
authors.lastname: Lakowski
authors.forename: Jane C
authors.initials: JC
authors.lastname: Sowden
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Pearson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000378:metabolism; D005434:Flow Cytometry; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009755:Night Blindness / Q000235:genetics / Q000601:surgery*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics / Q000601:surgery*; D064531:Peripherins; D017948:Retinal Rod Photoreceptor Cells / Q000637:transplantation* / Q000648:ultrastructure; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000601:surgery*; D015293:Transducin / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C453730:Crb1 protein, mouse; D044385:GTP-Binding Protein alpha Subunits; C488949:Gnat1 protein, mouse; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D064531:Peripherins; C578996:Prph2 protein, mouse; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D015293:Transducin; D020741:rho GTP-Binding Proteins