Gene augmentation therapy to rescue degenerative photoreceptors in a Cwc27 mutant mouse model

Jiaxiong Lu; Karen Q Zheng; Renae Elaine Bertrand; Joseph Quinlan; Salma Ferdous; Tanmay Srinivasan; Soo Oh; Keqing Wang; Rui Chen

doi:10.1016/j.exer.2023.109596

Gene augmentation therapy to rescue degenerative photoreceptors in a Cwc27 mutant mouse model

Exp Eye Res. 2023 Sep:234:109596. doi: 10.1016/j.exer.2023.109596. Epub 2023 Jul 20.

Authors

Jiaxiong Lu¹, Karen Q Zheng², Renae Elaine Bertrand¹, Joseph Quinlan³, Salma Ferdous⁴, Tanmay Srinivasan², Soo Oh⁴, Keqing Wang⁴, Rui Chen⁵

Affiliations

¹ Department 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.
² 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; Department of BioSciences, Rice University, Houston, TX, USA.
³ 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; Department of Bioengineering, Rice University, Houston, TX, USA.
⁴ 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.
⁵ Department 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. Electronic address: ruichen@bcm.edu.

PMID: 37479075
DOI: 10.1016/j.exer.2023.109596

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.

Keywords: AAV8; CWC27; Gene augmentation therapy; Photoreceptor; Spliceosome.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Disease Models, Animal
Electroretinography
Genetic Therapy / methods
Genetic Vectors
Mice
Retina / metabolism
Retinal Cone Photoreceptor Cells / metabolism
Retinal Degeneration* / genetics
Retinal Degeneration* / metabolism
Retinal Degeneration* / therapy

Abstract

Publication types

MeSH terms

Grants and funding