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Updated: Jul 22, 2025
Author Spotlight: Advancing Vision Restoration - Stem Cell-Based Therapy for Retinal Diseases
Published on: October 6, 2023
Gene augmentation therapy to rescue degenerative photoreceptors in a Cwc27 mutant mouse model
Jiaxiong Lu1, Karen Q Zheng2, Renae Elaine Bertrand1
1Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA; Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Abstract:
Previous reports have demonstrated that defects in the spliceosome-associated protein CWC27 can lead to the degeneration of retinal cells in Cwc27 mutant mouse models. However, it is unknown whether gene replacement therapy can rescue this phenotype. The purpose of this study was to evaluate whether AAV based gene therapy could rescue the retinal degeneration observed in Cwc27 mutant mice. By 6 months of age, Cwc27 mutant mice show a retinal degenerative phenotype, including morphological and functional abnormalities, primarily driven by the death of photoreceptors. We hypothesize that subretinal injection of AAV8 to drive exogenous CWC27 protein expression will improve the retinal phenotype. We evaluated these improvements after gene therapy with electroretinography (ERG) and histology, either hematoxylin and eosin (H&E) or immunostaining. In this study, we demonstrated that subretinal injection of AAV8-GRK-Cwc27-FLAG in mutant mice can improve the functionality and morphology of the retina. Immunostaining analyses revealed a notable decrease in photoreceptor degeneration, including cone cell degeneration, in the AAV-injected eyes compared to the PBS-injected eyes. Based on these results, gene replacement therapy could be a promising method for treating retinal degeneration caused by mutations in Cwc27.
Insights
Gene replacement therapy using AAV8 successfully rescued retinal degeneration in Cwc27 mutant mice. This treatment improved retinal function and morphology, offering a promising therapeutic strategy for CWC27-related eye diseases.
Area of Science:
- Ophthalmology
- Molecular Biology
- Genetics
Background:
- Defects in spliceosome-associated protein CWC27 cause retinal degeneration in mouse models.
- The potential of gene replacement therapy for CWC27-associated retinal disease remains unexplored.
Purpose of the Study:
- To investigate the efficacy of adeno-associated virus (AAV)-based gene therapy in rescuing retinal degeneration in Cwc27 mutant mice.
- To evaluate if restoring CWC27 protein expression can ameliorate the observed retinal phenotype.
Main Methods:
- Subretinal injection of AAV8 carrying the CWC27 gene into Cwc27 mutant mice.
- Assessment of retinal function using electroretinography (ERG).
- Histological and immunostaining analyses to evaluate retinal morphology and photoreceptor survival.
Main Results:
- AAV8-mediated CWC27 gene delivery significantly improved retinal morphology and function in treated mice.
- Histological analysis showed reduced photoreceptor degeneration, particularly in cone cells, in AAV-injected eyes compared to controls.
- Functional improvements were corroborated by electroretinography findings.
Conclusions:
- AAV-based gene replacement therapy is a viable and promising approach for treating retinal degeneration caused by CWC27 mutations.
- This study provides evidence for the therapeutic potential of targeting CWC27 deficiency in inherited retinal diseases.
