Trans-Sclera Electrical Stimulation Improves Retinal Function in a Mouse Model of Retinitis Pigmentosa

Liu, Feng; Zhang, Mengrong; Xiong, Guoyin; Han, Xiaohui; Lee, Vincent Wing Hong; So, Kwok‐Fai; Chiu, Kin; Xu, Ying

doi:10.3390/life12111917

Cited by 3 publications

(1 citation statement)

References 39 publications

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“…Similarly, we identified elevated b‐wave amplitude (28.54 ± 2.45 µV) in Figure 1F, in contrast to the retina of mice treated with GSH (13.56 ± 3.15 µV, p < 0.001) and PBS (6.64 ± 1.29 µV, p < 0.001). We performed black/white transition box behavioral experiments for further comprehensive analysis of visual functions, [ 24 ] which was based on the preference of mice for darkness. The distorted cones persisting in the rd1 mice's retinas were deficient in mediating light avoidance.…”

Section: Resultsmentioning

confidence: 99%

Alleviation of Photoreceptor Degeneration Based on Fullerenols in rd1 Mice by Reversing Mitochondrial Dysfunction via Modulation of Mitochondrial DNA Transcription and Leakage

Yang

Chen

Luodan

et al. 2023

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Poor therapeutic outcomes of antioxidants in ophthalmologic clinical applications, including glutathione during photoreceptor degeneration in retinitis pigmentosa (RP), are caused by limited anti‐oxidative capacity. In this study, fullerenols are synthesized and proven to be highly efficient in vitro radical scavengers. Fullerenol‐based intravitreal injections significantly improve the flash electroretinogram and light/dark transition tests performed for 28 days on rd1 mice, reduce the thinning of retinal outer nuclear layers, and preserve the Rhodopsin, Gnat‐1, and Arrestin expressions of photoreceptors. RNA‐sequencing, RT‐qPCR, and Western blotting validate that mitochondrial DNA (mt‐DNA)‐encoded genes of the electron transport chain (ETC), such as mt‐Nd4l, mt‐Co1, mt‐Cytb, and mt‐Atp6, are drastically downregulated in the retinas of rd1 mice, whereas nuclear DNA (n‐DNA)‐encoded genes, such as Ndufa1 and Atp5g3, are abnormally upregulated. Fullerenols thoroughly reverse the abnormal mt‐DNA and n‐DNA expression patterns of the ETC and restore mitochondrial function in degenerating photoreceptors. Additionally, fullerenols simultaneously repress Flap endonuclease 1 (FEN1)‐mediated mt‐DNA cleavage and mt‐DNA leakage via voltage‐dependent anion channel (VDAC) pores by downregulating the transcription of Fen1 and Vdac1, thereby inactivating the downstream pro‐inflammatory cGAS‐STING pathway. These findings demonstrate that fullerenols can effectively alleviate photoreceptor degeneration in rd1 mice and serve as a viable treatment for RP.

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Section: Resultsmentioning

confidence: 99%

Alleviation of Photoreceptor Degeneration Based on Fullerenols in rd1 Mice by Reversing Mitochondrial Dysfunction via Modulation of Mitochondrial DNA Transcription and Leakage

Yang

Chen

Luodan

et al. 2023

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Translatability barriers between preclinical and clinical trials of AAV gene therapy in inherited retinal diseases

et al. 2023

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Development of TRIB3-Based Therapy as a Gene-Independent Approach to Treat Retinal Degenerative Disorders

Ung,

Starr,

Zhylkibayev

et al. 2024

IJMS

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Inherited retinal degeneration (RD) constitutes a heterogeneous group of genetic retinal degenerative disorders. The molecular mechanisms underlying RD encompass a diverse spectrum of cellular signaling, with the unfolded protein response (UPR) identified as a common signaling pathway chronically activated in degenerating retinas. TRIB3 has been recognized as a key mediator of the PERK UPR arm, influencing various metabolic pathways, such as insulin signaling, lipid metabolism, and glucose homeostasis, by acting as an AKT pseudokinase that prevents the activation of the AKT → mTOR axis. This study aimed to develop a gene-independent approach targeting the UPR TRIB3 mediator previously tested by our group using a genetic approach in mice with RD. The goal was to validate a therapeutic approach targeting TRIB3 interactomes through the pharmacological targeting of EGFR-TRIB3 and delivering cell-penetrating peptides targeting TRIB3 → AKT. The study employed rd10 and P23H RHO mice, with afatinib treatment conducted in p15 rd10 mice through daily intraperitoneal injections. P15 P23H RHO mice received intraocular injections of cell-penetrating peptides twice at a 2-week interval. Our study revealed that both strategies successfully targeted TRIB3 interactomes, leading to an improvement in scotopic A- and B-wave ERG recordings. Additionally, the afatinib-treated mice manifested enhanced photopic ERG amplitudes accompanied by a delay in photoreceptor cell loss. The treated rd10 retinas also showed increased PDE6β and RHO staining, along with an elevation in total PDE activity in the retinas. Consequently, our study demonstrated the feasibility of a gene-independent strategy to target common signaling in degenerating retinas by employing a TRIB3-based therapeutic approach that delays retinal function and photoreceptor cell loss in two RD models.

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Trans-Sclera Electrical Stimulation Improves Retinal Function in a Mouse Model of Retinitis Pigmentosa

Cited by 3 publications

References 39 publications

Alleviation of Photoreceptor Degeneration Based on Fullerenols in rd1 Mice by Reversing Mitochondrial Dysfunction via Modulation of Mitochondrial DNA Transcription and Leakage

Alleviation of Photoreceptor Degeneration Based on Fullerenols in rd1 Mice by Reversing Mitochondrial Dysfunction via Modulation of Mitochondrial DNA Transcription and Leakage

Translatability barriers between preclinical and clinical trials of AAV gene therapy in inherited retinal diseases

Development of TRIB3-Based Therapy as a Gene-Independent Approach to Treat Retinal Degenerative Disorders

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