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Characterization of a novel Pde6b-deficient rat model of retinal degeneration and treatment with adeno-associated virus (AAV) gene therapy.
- Source :
-
Gene therapy [Gene Ther] 2023 Apr; Vol. 30 (3-4), pp. 362-368. Date of Electronic Publication: 2022 Sep 29. - Publication Year :
- 2023
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Abstract
- In humans, mutations in the beta subunit of cGMP-phosphodiesterase type 6 (PDE6B) cause autosomal recessive retinitis pigmentosa (RP), which typically has an aggressive clinical course of early-onset severe vision loss due to rapid photoreceptor degeneration. In this study, we describe the generation of a novel Pde6b-deficient rat model using CRISPR-Cas9 genome editing. We characterize the model at multiple time points using clinical imaging modalities as well as histology with immunohistochemistry to show rapid photoreceptor degeneration compared to wild-type and heterozygous animals. We describe the manufacture of two different adeno-associated viral (AAV) vectors (AAV2/1, AAV2/5) under current Good Manufacturing Practices (cGMP) and demonstrate their ability to drive human PDE6B expression in vivo. We further demonstrate the ability of AAV-mediated subretinal gene therapy to delay photoreceptor loss in Pde6b-deficient rats compared to untreated controls. However, severe progressive photoreceptor loss was noted even in treated eyes, likely due to the aggressive nature of the disease. These data provide useful preclinical data to guide the development of potential human gene therapy for PDE6B-associated RP. In addition, the rapid photoreceptor degeneration of the Pde6b-deficient rat with intact inner retina may provide a useful model for the study of cell replacement strategies.<br /> (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Rats
Animals
Humans
Dependovirus genetics
Retina metabolism
Genetic Therapy methods
Disease Models, Animal
Cyclic Nucleotide Phosphodiesterases, Type 6 genetics
Cyclic Nucleotide Phosphodiesterases, Type 6 metabolism
Retinal Degeneration genetics
Retinal Degeneration therapy
Retinitis Pigmentosa genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5462
- Volume :
- 30
- Issue :
- 3-4
- Database :
- MEDLINE
- Journal :
- Gene therapy
- Publication Type :
- Academic Journal
- Accession number :
- 36175490
- Full Text :
- https://doi.org/10.1038/s41434-022-00365-y