Deep phenotyping of the Cdhr1−/− mouse validates its use in pre-clinical studies for human CDHR1-associated retinal degeneration
Purpose To validate the Cdhr1−/− mouse as a model for human CDHR1-associated retinal degeneration, which may present as cone-rod dystrophy or geographic atrophy. Methods Deep phenotyping of Cdhr1−/− (n = 56) and C57BL6J wildtype control mice (n = 45) was undertaken using in vivo multimodal retinal...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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Elsevier
2021
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| _version_ | 1826307638804086784 |
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| author | Yusuf, I McClements, M Maclaren, R Charbel Issa, P |
| author_facet | Yusuf, I McClements, M Maclaren, R Charbel Issa, P |
| author_sort | Yusuf, I |
| collection | OXFORD |
| description | Purpose
To validate the Cdhr1−/− mouse as a model for human CDHR1-associated retinal degeneration, which may present as cone-rod dystrophy or geographic atrophy.
Methods
Deep phenotyping of Cdhr1−/− (n = 56) and C57BL6J wildtype control mice (n = 45) was undertaken using in vivo multimodal retinal imaging and dark- and light-adapted electroretinography (ERG) over 15 months to evaluate rod- and cone-photoreceptor responses and retinal morphology.
Results
Cdhr1−/− retinas exhibited outer retinal thinning on optical coherence tomography (OCT) at 1-month versus C57BL6J (mean 14.6% reduction; P < 0.0001), with progressive degeneration to 15 months. The OCT layer representing photoreceptor outer segments was more significantly shortened in Cdhr1−/− eyes at 1 month (mean 33.7% reduction; P < 0.0001), remained stable to 3 months and was not identifiable at later timepoints. Outer retinal thinning was more pronounced at inferior versus superior retinal locations in Cdhr1−/− eyes (P < 0.002 at 3–9 months). Dark-adapted ERG identified severe functional deficits in Cdhr1−/− mice at 1 month of age versus C57BL6J (mean 62% reduction) that continued to decline to 15 months (P < 0.0001). Light-adapted flicker identified severe deficits in cone function at 1 month (mean 70% reduction), with improved function to 3 months followed by progressive decline (P < 0.0001).
Conclusions
The Cdhr1−/− mouse exhibits structural and functional evidence of progressive outer retinal degeneration at a slow rate. Early functional deficits affecting both rod and cone photoreceptors in the context of relatively mild structural changes reflect the human phenotype. This study validates the use of the Cdhr1−/− mouse for the pre-clinical evaluation of therapeutics for human CDHR1-associated retinal degeneration.
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| first_indexed | 2024-03-07T07:06:09Z |
| format | Journal article |
| id | oxford-uuid:63698870-9e67-4512-9e32-2338bff23b2b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:06:09Z |
| publishDate | 2021 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:63698870-9e67-4512-9e32-2338bff23b2b2022-05-06T08:38:54ZDeep phenotyping of the Cdhr1−/− mouse validates its use in pre-clinical studies for human CDHR1-associated retinal degenerationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:63698870-9e67-4512-9e32-2338bff23b2bEnglishSymplectic ElementsElsevier2021Yusuf, IMcClements, MMaclaren, RCharbel Issa, PPurpose To validate the Cdhr1−/− mouse as a model for human CDHR1-associated retinal degeneration, which may present as cone-rod dystrophy or geographic atrophy. Methods Deep phenotyping of Cdhr1−/− (n = 56) and C57BL6J wildtype control mice (n = 45) was undertaken using in vivo multimodal retinal imaging and dark- and light-adapted electroretinography (ERG) over 15 months to evaluate rod- and cone-photoreceptor responses and retinal morphology. Results Cdhr1−/− retinas exhibited outer retinal thinning on optical coherence tomography (OCT) at 1-month versus C57BL6J (mean 14.6% reduction; P < 0.0001), with progressive degeneration to 15 months. The OCT layer representing photoreceptor outer segments was more significantly shortened in Cdhr1−/− eyes at 1 month (mean 33.7% reduction; P < 0.0001), remained stable to 3 months and was not identifiable at later timepoints. Outer retinal thinning was more pronounced at inferior versus superior retinal locations in Cdhr1−/− eyes (P < 0.002 at 3–9 months). Dark-adapted ERG identified severe functional deficits in Cdhr1−/− mice at 1 month of age versus C57BL6J (mean 62% reduction) that continued to decline to 15 months (P < 0.0001). Light-adapted flicker identified severe deficits in cone function at 1 month (mean 70% reduction), with improved function to 3 months followed by progressive decline (P < 0.0001). Conclusions The Cdhr1−/− mouse exhibits structural and functional evidence of progressive outer retinal degeneration at a slow rate. Early functional deficits affecting both rod and cone photoreceptors in the context of relatively mild structural changes reflect the human phenotype. This study validates the use of the Cdhr1−/− mouse for the pre-clinical evaluation of therapeutics for human CDHR1-associated retinal degeneration. |
| spellingShingle | Yusuf, I McClements, M Maclaren, R Charbel Issa, P Deep phenotyping of the Cdhr1−/− mouse validates its use in pre-clinical studies for human CDHR1-associated retinal degeneration |
| title | Deep phenotyping of the Cdhr1−/− mouse validates its use in pre-clinical studies for human CDHR1-associated retinal degeneration |
| title_full | Deep phenotyping of the Cdhr1−/− mouse validates its use in pre-clinical studies for human CDHR1-associated retinal degeneration |
| title_fullStr | Deep phenotyping of the Cdhr1−/− mouse validates its use in pre-clinical studies for human CDHR1-associated retinal degeneration |
| title_full_unstemmed | Deep phenotyping of the Cdhr1−/− mouse validates its use in pre-clinical studies for human CDHR1-associated retinal degeneration |
| title_short | Deep phenotyping of the Cdhr1−/− mouse validates its use in pre-clinical studies for human CDHR1-associated retinal degeneration |
| title_sort | deep phenotyping of the cdhr1 mouse validates its use in pre clinical studies for human cdhr1 associated retinal degeneration |
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