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Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model

Patients with progressive neurodegenerative disorder retinitis pigmentosa (RP) are diagnosed in the midst of ongoing retinal degeneration and remodeling. Here, we used a Pde6b-deficient RP gene therapy mouse model to test whether treatment at late disease stages can halt photoreceptor degeneration a...

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Autores principales: Kajtna, Jacqueline, Tsang, Stephen H., Koch, Susanne F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8866266/
https://www.ncbi.nlm.nih.gov/pubmed/35195763
http://dx.doi.org/10.1007/s00018-022-04161-0
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author Kajtna, Jacqueline
Tsang, Stephen H.
Koch, Susanne F.
author_facet Kajtna, Jacqueline
Tsang, Stephen H.
Koch, Susanne F.
author_sort Kajtna, Jacqueline
collection PubMed
description Patients with progressive neurodegenerative disorder retinitis pigmentosa (RP) are diagnosed in the midst of ongoing retinal degeneration and remodeling. Here, we used a Pde6b-deficient RP gene therapy mouse model to test whether treatment at late disease stages can halt photoreceptor degeneration and degradative remodeling, while sustaining constructive remodeling and restoring function. We demonstrated that when fewer than 13% of rods remain, our genetic rescue halts photoreceptor degeneration, electroretinography (ERG) functional decline and inner retinal remodeling. In addition, in a water maze test, the performance of mice treated at 16 weeks of age or earlier was indistinguishable from wild type. In contrast, no efficacy was apparent in mice treated at 24 weeks of age, suggesting the photoreceptors had reached a point of no return. Further, remodeling in the retinal pigment epithelium (RPE) and retinal vasculature was not halted at 16 or 24 weeks of age, although there appeared to be some slowing of blood vessel degradation. These data suggest a novel working model in which restoration of clinically significant visual function requires only modest threshold numbers of resilient photoreceptors, halting of destructive remodeling and sustained constructive remodeling. These novel findings define the potential and limitations of RP treatment and suggest possible nonphotoreceptor targets for gene therapy optimization. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04161-0.
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spelling pubmed-88662662022-03-02 Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model Kajtna, Jacqueline Tsang, Stephen H. Koch, Susanne F. Cell Mol Life Sci Original Article Patients with progressive neurodegenerative disorder retinitis pigmentosa (RP) are diagnosed in the midst of ongoing retinal degeneration and remodeling. Here, we used a Pde6b-deficient RP gene therapy mouse model to test whether treatment at late disease stages can halt photoreceptor degeneration and degradative remodeling, while sustaining constructive remodeling and restoring function. We demonstrated that when fewer than 13% of rods remain, our genetic rescue halts photoreceptor degeneration, electroretinography (ERG) functional decline and inner retinal remodeling. In addition, in a water maze test, the performance of mice treated at 16 weeks of age or earlier was indistinguishable from wild type. In contrast, no efficacy was apparent in mice treated at 24 weeks of age, suggesting the photoreceptors had reached a point of no return. Further, remodeling in the retinal pigment epithelium (RPE) and retinal vasculature was not halted at 16 or 24 weeks of age, although there appeared to be some slowing of blood vessel degradation. These data suggest a novel working model in which restoration of clinically significant visual function requires only modest threshold numbers of resilient photoreceptors, halting of destructive remodeling and sustained constructive remodeling. These novel findings define the potential and limitations of RP treatment and suggest possible nonphotoreceptor targets for gene therapy optimization. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04161-0. Springer International Publishing 2022-02-23 2022 /pmc/articles/PMC8866266/ /pubmed/35195763 http://dx.doi.org/10.1007/s00018-022-04161-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Kajtna, Jacqueline
Tsang, Stephen H.
Koch, Susanne F.
Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model
title Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model
title_full Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model
title_fullStr Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model
title_full_unstemmed Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model
title_short Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model
title_sort late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8866266/
https://www.ncbi.nlm.nih.gov/pubmed/35195763
http://dx.doi.org/10.1007/s00018-022-04161-0
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