Gene Therapy for Rdh12-Associated Retinal Diseases Helps to Delay Retinal Degeneration and Vision Loss

Abstract

Purpose

The aim of study was to establish Rdh12-associated inherited retinal disease (Rdh12-IRD) mouse model and to identify the best timepoint for gene therapy.

Methods

We induced retinal degeneration in Rdh12^−/− mice using a bright light. We clarified the establishment of Rdh12-IRD mouse model by analyzing the thickness of retinal layers and electroretinography (ERG). Rdh12-IRD mice received a subretinal injection of adeno-associated virus 2/8-packaged Rdh12 cDNA for treatment. We evaluated the visual function and retinal structure in the treated and untreated eyes to identify the best timepoint for gene therapy.

Results

Rdh12-IRD mice showed significant differences in ERG amplitudes and photoreceptor survival compared to Rdh12^+/+ mice. Preventive gene therapy not only maintained normal visual function but also prevented photoreceptor loss. Salvage gene therapy could not reverse the retinal degeneration phenotype of Rdh12-IRD mice, but it could slow down the loss of visual function.

Conclusion

The light-induced retinal degeneration in our Rdh12^−/− mice indicated that a defect in Rdh12 alone was sufficient to cause visual dysfunction and photoreceptor degeneration, which reproduced the phenotypes observed in RDH12-IRD patients. This model is suitable for gene therapy studies. Early treatment of the primary Rdh12 defect helps to delay the later onset of photoreceptor degeneration and maintains visual function in Rdh12-IRD mice.

Keywords:

• Rdh12
• retinal diseases
• mouse model
• gene therapy

Acknowledgments

The authors thank Xiangtian Zhou from Wenzhou Medical University for providing the support on our electroretinogram detection.

Abbreviations

IRDs, inherited retinal diseases; LD, light-induced retinal degeneration; ERG, electroretinography; RDH12, retinol dehydrogenase 12; LCA13, Leber congenital amaurosis type 13; ONL, outer nuclear layer.

Disclosure

Hongyu Chen’s current affiliation is at National Clinical Research Center for Child Health, The Children’s Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China. Junhui Sun’s current affiliation is at Reproductive Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. The authors report no conflicts of interest in this work.

Additional information

Funding

The study was supported by grants from the Science and Technology Project of Zhejiang Province (2018C37121), Natural Science Foundation of Zhejiang Province (LZ14C060001) and National Natural Science Foundation of China (31371271).