Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (8): 2408-2419.doi: 10.4103/NRR.NRR-D-23-01301

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AAV2-PDE6B restores retinal structure and function in the retinal degeneration 10 mouse model of retinitis pigmentosa by promoting phototransduction and inhibiting apoptosis

Ruiqi Qiu1, 2, #, Mingzhu Yang1, 2, #, Xiuxiu Jin1, 2, 3, Jingyang Liu1, 2, Weiping Wang1, 2, Xiaoli Zhang1, 4, Jinfeng Han1, 4, Bo Lei1, 2, 3, 4, *   

  1. 1 Henan Eye Hospital, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; 2 Eye Institute, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan Province, China; 3 Branch of National Clinical Research Center for Ocular Disease, Henan Provincial People’s Hospital, Zhengzhou, Henan Province, China; 4 Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan Province, China
  • Online:2025-08-15 Published:2024-12-14
  • Contact: Bo Lei, MD, PhD, FARVO, bolei99@126.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82071008 (to BL) and 82004001 (to XJ); Medical Science and Technology Program of Health Commission of Henan Province, No. LHGJ20210072 (to RQ); and Science and Technology Department of Henan Province, No. 212102310307 (to XJ).

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Abstract: Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death. However, there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation. Adeno-associated virus (AAV)-mediated gene therapy is a promising strategy for treating retinitis pigmentosa. The aim of this study was to explore the molecular mechanisms by which AAV2- PDE6B rescues retinal function. To do this, we injected retinal degeneration 10 (rd10) mice subretinally with AAV2-PDE6B and assessed the therapeutic effects on retinal function and structure using dark- and light-adapted electroretinogram, optical coherence tomography, and immunofluorescence. Data-independent acquisition-mass spectrometry-based proteomic analysis was conducted to investigate protein expression levels and pathway enrichment, and the results from this analysis were verified by real-time polymerase chain reaction and western blotting. AAV2-PDE6B injection significantly upregulated PDE6β expression, preserved electroretinogram responses, and preserved outer nuclear layer thickness in rd10 mice. Differentially expressed proteins between wild-type and rd10 mice were closely related to visual perception, and treating rd10 mice with AAV2-PDE6B restored differentially expressed protein expression to levels similar to those seen in wild-type mice. Kyoto Encyclopedia of Genes and Genome analysis showed that the differentially expressed proteins whose expression was most significantly altered by AAV2-PDE6B injection were enriched in phototransduction pathways. Furthermore, the phototransductionrelated proteins Pde6α, Rom1, Rho, Aldh1a1, and Rbp1 exhibited opposite expression patterns in rd10 mice with or without AAV2-PDE6B treatment. Finally, Bax/Bcl-2, p-ERK/ERK, and p-c-Fos/c-Fos expression levels decreased in rd10 mice following AAV2-PDE6B treatment. Our data suggest that AAV2-PDE6B-mediated gene therapy promotes phototransduction and inhibits apoptosis by inhibiting the ERK signaling pathway and upregulating Bcl-2/Bax expression in retinitis pigmentosa.

Key words: apoptosis,  AAV2-PDE6B,  ERK1/2,  gene therapy,  phototransduction,  proteomics,  rd10,  retinitis pigmentosa