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Repair of the degenerate retina by photoreceptor transplantation

Repair of the degenerate retina by photoreceptor transplantation
Repair of the degenerate retina by photoreceptor transplantation

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.

Animals, Blotting, Western, Cell Count, Cyclic Nucleotide Phosphodiesterases, Type 6/metabolism, Flow Cytometry, GTP-Binding Protein alpha Subunits/genetics, Intermediate Filament Proteins/metabolism, Membrane Glycoproteins/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Confocal, Microscopy, Electron, Transmission, Nerve Tissue Proteins/metabolism, Night Blindness/genetics, Optic Atrophy, Hereditary, Leber/genetics, Peripherins, Retinal Rod Photoreceptor Cells/transplantation, Retinitis Pigmentosa/genetics, Transducin/genetics, Treatment Outcome, rho GTP-Binding Proteins/genetics
0027-8424
354-359
Barber, Amanda C.
60076cd1-0d5b-47d4-a4e1-b7251e5e2f8f
Hippert, Claire
6aae1216-5503-46fb-830b-f170ae15b1e1
Duran, Yanai
16d2c404-658b-44e7-9bf0-ddf55952777a
West, Emma L.
e9fb2858-50ad-46a1-9aca-5b57d9b32042
Bainbridge, James W B
be3077b2-2b9c-41de-9f1c-ecb6dda9ad82
Warre-Cornish, Katherine
dd8db625-47ae-4d49-9d04-c48157b12973
Luhmann, Ulrich F. O.
5ebd9f18-a33c-460a-b2a2-fe44236ad4be
Lakowski, Jorn
1856e739-982a-412a-87c7-abf1610f5384
Sowden, Jane C.
e042184a-dbe3-4a58-9f91-c31a5463b893
Ali, Robin R.
bddfdcbe-75ce-4264-80cc-c9ef1d6c9d7d
Pearson, Rachael A.
4b8c2476-e361-42e4-a4cb-71208646d06a
Barber, Amanda C.
60076cd1-0d5b-47d4-a4e1-b7251e5e2f8f
Hippert, Claire
6aae1216-5503-46fb-830b-f170ae15b1e1
Duran, Yanai
16d2c404-658b-44e7-9bf0-ddf55952777a
West, Emma L.
e9fb2858-50ad-46a1-9aca-5b57d9b32042
Bainbridge, James W B
be3077b2-2b9c-41de-9f1c-ecb6dda9ad82
Warre-Cornish, Katherine
dd8db625-47ae-4d49-9d04-c48157b12973
Luhmann, Ulrich F. O.
5ebd9f18-a33c-460a-b2a2-fe44236ad4be
Lakowski, Jorn
1856e739-982a-412a-87c7-abf1610f5384
Sowden, Jane C.
e042184a-dbe3-4a58-9f91-c31a5463b893
Ali, Robin R.
bddfdcbe-75ce-4264-80cc-c9ef1d6c9d7d
Pearson, Rachael A.
4b8c2476-e361-42e4-a4cb-71208646d06a

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. and Pearson, Rachael A. (2013) Repair of the degenerate retina by photoreceptor transplantation. Proceedings of the National Academy of Sciences of the United States of America, 110 (1), 354-359. (doi:10.1073/pnas.1212677110).

Record type: Article

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.

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More information

Accepted/In Press date: 14 November 2012
Published date: 2 January 2013
Keywords: Animals, Blotting, Western, Cell Count, Cyclic Nucleotide Phosphodiesterases, Type 6/metabolism, Flow Cytometry, GTP-Binding Protein alpha Subunits/genetics, Intermediate Filament Proteins/metabolism, Membrane Glycoproteins/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Confocal, Microscopy, Electron, Transmission, Nerve Tissue Proteins/metabolism, Night Blindness/genetics, Optic Atrophy, Hereditary, Leber/genetics, Peripherins, Retinal Rod Photoreceptor Cells/transplantation, Retinitis Pigmentosa/genetics, Transducin/genetics, Treatment Outcome, rho GTP-Binding Proteins/genetics

Identifiers

Local EPrints ID: 431143
URI: http://eprints.soton.ac.uk/id/eprint/431143
ISSN: 0027-8424
PURE UUID: c698700d-9ac8-451e-8f15-f17ec5a2cb11
ORCID for Jorn Lakowski: ORCID iD orcid.org/0000-0003-4214-7580

Catalogue record

Date deposited: 24 May 2019 16:30
Last modified: 10 Nov 2021 03:50

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Contributors

Author: Amanda C. Barber
Author: Claire Hippert
Author: Yanai Duran
Author: Emma L. West
Author: James W B Bainbridge
Author: Katherine Warre-Cornish
Author: Ulrich F. O. Luhmann
Author: Jorn Lakowski ORCID iD
Author: Jane C. Sowden
Author: Robin R. Ali
Author: Rachael A. Pearson

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