Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa
Abstract Retinitis pigmentosa is an inherited photoreceptor degeneration that begins with rod loss followed by cone loss. This cell loss greatly diminishes vision, with most patients becoming legally blind. Gene therapies are being developed, but it is unknown how retinal function depends on the tim...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44063-8 |
| _version_ | 1797388183664590848 |
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| author | Miranda L. Scalabrino Mishek Thapa Tian Wang Alapakkam P. Sampath Jeannie Chen Greg D. Field |
| author_facet | Miranda L. Scalabrino Mishek Thapa Tian Wang Alapakkam P. Sampath Jeannie Chen Greg D. Field |
| author_sort | Miranda L. Scalabrino |
| collection | DOAJ |
| description | Abstract Retinitis pigmentosa is an inherited photoreceptor degeneration that begins with rod loss followed by cone loss. This cell loss greatly diminishes vision, with most patients becoming legally blind. Gene therapies are being developed, but it is unknown how retinal function depends on the time of intervention. To uncover this dependence, we utilize a mouse model of retinitis pigmentosa capable of artificial genetic rescue. This model enables a benchmark of best-case gene therapy by removing variables that complicate answering this question. Complete genetic rescue was performed at 25%, 50%, and 70% rod loss (early, mid and late, respectively). Early and mid treatment restore retinal output to near wild-type levels. Late treatment retinas exhibit continued, albeit slowed, loss of sensitivity and signal fidelity among retinal ganglion cells, as well as persistent gliosis. We conclude that gene replacement therapies delivered after 50% rod loss are unlikely to restore visual function to normal. This is critical information for administering gene therapies to rescue vision. |
| first_indexed | 2024-03-08T22:37:04Z |
| format | Article |
| id | doaj.art-1aa9987457344b90b4f65e7efd14f6ff |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T22:37:04Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-1aa9987457344b90b4f65e7efd14f6ff2023-12-17T12:22:26ZengNature PortfolioNature Communications2041-17232023-12-0114111110.1038/s41467-023-44063-8Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosaMiranda L. Scalabrino0Mishek Thapa1Tian Wang2Alapakkam P. Sampath3Jeannie Chen4Greg D. Field5Stein Eye Institute, Department of Ophthalmology, University of CaliforniaStein Eye Institute, Department of Ophthalmology, University of CaliforniaZilkha Neurogenetic Institute, Keck School of Medicine, University of Southern CaliforniaStein Eye Institute, Department of Ophthalmology, University of CaliforniaZilkha Neurogenetic Institute, Keck School of Medicine, University of Southern CaliforniaStein Eye Institute, Department of Ophthalmology, University of CaliforniaAbstract Retinitis pigmentosa is an inherited photoreceptor degeneration that begins with rod loss followed by cone loss. This cell loss greatly diminishes vision, with most patients becoming legally blind. Gene therapies are being developed, but it is unknown how retinal function depends on the time of intervention. To uncover this dependence, we utilize a mouse model of retinitis pigmentosa capable of artificial genetic rescue. This model enables a benchmark of best-case gene therapy by removing variables that complicate answering this question. Complete genetic rescue was performed at 25%, 50%, and 70% rod loss (early, mid and late, respectively). Early and mid treatment restore retinal output to near wild-type levels. Late treatment retinas exhibit continued, albeit slowed, loss of sensitivity and signal fidelity among retinal ganglion cells, as well as persistent gliosis. We conclude that gene replacement therapies delivered after 50% rod loss are unlikely to restore visual function to normal. This is critical information for administering gene therapies to rescue vision.https://doi.org/10.1038/s41467-023-44063-8 |
| spellingShingle | Miranda L. Scalabrino Mishek Thapa Tian Wang Alapakkam P. Sampath Jeannie Chen Greg D. Field Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa Nature Communications |
| title | Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa |
| title_full | Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa |
| title_fullStr | Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa |
| title_full_unstemmed | Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa |
| title_short | Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa |
| title_sort | late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa |
| url | https://doi.org/10.1038/s41467-023-44063-8 |
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